IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.5324T>A (p.Met1775Lys)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Aug 2015 by
Evidence-based…
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007294.4(BRCA1):c.5324T>A (p.Met1775Lys)
Variation ID: 17695 Accession: VCV000017695.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q21.31 17: 43051071 (GRCh38) [ NCBI UCSC ] 17: 41203088 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 27, 2014 May 1, 2024 Aug 10, 2015 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.5324T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Met1775Lys missense NM_001407571.1:c.5111T>A NP_001394500.1:p.Met1704Lys missense NM_001407581.1:c.5390T>A NP_001394510.1:p.Met1797Lys missense NM_001407582.1:c.5390T>A NP_001394511.1:p.Met1797Lys missense NM_001407583.1:c.5387T>A NP_001394512.1:p.Met1796Lys missense NM_001407585.1:c.5387T>A NP_001394514.1:p.Met1796Lys missense NM_001407587.1:c.5387T>A NP_001394516.1:p.Met1796Lys missense NM_001407590.1:c.5384T>A NP_001394519.1:p.Met1795Lys missense NM_001407591.1:c.5384T>A NP_001394520.1:p.Met1795Lys missense NM_001407593.1:c.5324T>A NP_001394522.1:p.Met1775Lys missense NM_001407594.1:c.5324T>A NP_001394523.1:p.Met1775Lys missense NM_001407596.1:c.5324T>A NP_001394525.1:p.Met1775Lys missense NM_001407597.1:c.5324T>A NP_001394526.1:p.Met1775Lys missense NM_001407598.1:c.5324T>A NP_001394527.1:p.Met1775Lys missense NM_001407602.1:c.5324T>A NP_001394531.1:p.Met1775Lys missense NM_001407603.1:c.5324T>A NP_001394532.1:p.Met1775Lys missense NM_001407605.1:c.5324T>A NP_001394534.1:p.Met1775Lys missense NM_001407610.1:c.5321T>A NP_001394539.1:p.Met1774Lys missense NM_001407611.1:c.5321T>A NP_001394540.1:p.Met1774Lys missense NM_001407612.1:c.5321T>A NP_001394541.1:p.Met1774Lys missense NM_001407613.1:c.5321T>A NP_001394542.1:p.Met1774Lys missense NM_001407614.1:c.5321T>A NP_001394543.1:p.Met1774Lys missense NM_001407615.1:c.5321T>A NP_001394544.1:p.Met1774Lys missense NM_001407616.1:c.5321T>A NP_001394545.1:p.Met1774Lys missense NM_001407617.1:c.5321T>A NP_001394546.1:p.Met1774Lys missense NM_001407618.1:c.5321T>A NP_001394547.1:p.Met1774Lys missense NM_001407619.1:c.5321T>A NP_001394548.1:p.Met1774Lys missense NM_001407620.1:c.5321T>A NP_001394549.1:p.Met1774Lys missense NM_001407621.1:c.5321T>A NP_001394550.1:p.Met1774Lys missense NM_001407622.1:c.5321T>A NP_001394551.1:p.Met1774Lys missense NM_001407623.1:c.5321T>A NP_001394552.1:p.Met1774Lys missense NM_001407624.1:c.5321T>A NP_001394553.1:p.Met1774Lys missense NM_001407625.1:c.5321T>A NP_001394554.1:p.Met1774Lys missense NM_001407626.1:c.5321T>A NP_001394555.1:p.Met1774Lys missense NM_001407627.1:c.5318T>A NP_001394556.1:p.Met1773Lys missense NM_001407628.1:c.5318T>A NP_001394557.1:p.Met1773Lys missense NM_001407629.1:c.5318T>A NP_001394558.1:p.Met1773Lys missense NM_001407630.1:c.5318T>A NP_001394559.1:p.Met1773Lys missense NM_001407631.1:c.5318T>A NP_001394560.1:p.Met1773Lys missense NM_001407632.1:c.5318T>A NP_001394561.1:p.Met1773Lys missense NM_001407633.1:c.5318T>A NP_001394562.1:p.Met1773Lys missense NM_001407634.1:c.5318T>A NP_001394563.1:p.Met1773Lys missense NM_001407635.1:c.5318T>A NP_001394564.1:p.Met1773Lys missense NM_001407636.1:c.5318T>A NP_001394565.1:p.Met1773Lys missense NM_001407637.1:c.5318T>A NP_001394566.1:p.Met1773Lys missense NM_001407638.1:c.5318T>A NP_001394567.1:p.Met1773Lys missense NM_001407639.1:c.5318T>A NP_001394568.1:p.Met1773Lys missense NM_001407640.1:c.5318T>A NP_001394569.1:p.Met1773Lys missense NM_001407641.1:c.5318T>A NP_001394570.1:p.Met1773Lys missense NM_001407642.1:c.5318T>A NP_001394571.1:p.Met1773Lys missense NM_001407644.1:c.5315T>A NP_001394573.1:p.Met1772Lys missense NM_001407645.1:c.5315T>A NP_001394574.1:p.Met1772Lys missense NM_001407646.1:c.5312T>A NP_001394575.1:p.Met1771Lys missense NM_001407647.1:c.5309T>A NP_001394576.1:p.Met1770Lys missense NM_001407648.1:c.5267T>A NP_001394577.1:p.Met1756Lys missense NM_001407649.1:c.5264T>A NP_001394578.1:p.Met1755Lys missense NM_001407652.1:c.5246T>A NP_001394581.1:p.Met1749Lys missense NM_001407653.1:c.5246T>A NP_001394582.1:p.Met1749Lys missense NM_001407654.1:c.5246T>A NP_001394583.1:p.Met1749Lys missense NM_001407655.1:c.5246T>A NP_001394584.1:p.Met1749Lys missense NM_001407656.1:c.5243T>A NP_001394585.1:p.Met1748Lys missense NM_001407657.1:c.5243T>A NP_001394586.1:p.Met1748Lys missense NM_001407658.1:c.5243T>A NP_001394587.1:p.Met1748Lys missense NM_001407659.1:c.5240T>A NP_001394588.1:p.Met1747Lys missense NM_001407660.1:c.5240T>A NP_001394589.1:p.Met1747Lys missense NM_001407661.1:c.5240T>A NP_001394590.1:p.Met1747Lys missense NM_001407662.1:c.5240T>A NP_001394591.1:p.Met1747Lys missense NM_001407663.1:c.5240T>A NP_001394592.1:p.Met1747Lys missense NM_001407664.1:c.5201T>A NP_001394593.1:p.Met1734Lys missense NM_001407665.1:c.5201T>A NP_001394594.1:p.Met1734Lys missense NM_001407666.1:c.5201T>A NP_001394595.1:p.Met1734Lys missense NM_001407667.1:c.5201T>A NP_001394596.1:p.Met1734Lys missense NM_001407668.1:c.5201T>A NP_001394597.1:p.Met1734Lys missense NM_001407669.1:c.5201T>A NP_001394598.1:p.Met1734Lys missense NM_001407670.1:c.5198T>A NP_001394599.1:p.Met1733Lys missense NM_001407671.1:c.5198T>A NP_001394600.1:p.Met1733Lys missense NM_001407672.1:c.5198T>A NP_001394601.1:p.Met1733Lys missense NM_001407673.1:c.5198T>A NP_001394602.1:p.Met1733Lys missense NM_001407674.1:c.5198T>A NP_001394603.1:p.Met1733Lys missense NM_001407675.1:c.5198T>A NP_001394604.1:p.Met1733Lys missense NM_001407676.1:c.5198T>A NP_001394605.1:p.Met1733Lys missense NM_001407677.1:c.5198T>A NP_001394606.1:p.Met1733Lys missense NM_001407678.1:c.5198T>A NP_001394607.1:p.Met1733Lys missense NM_001407679.1:c.5198T>A NP_001394608.1:p.Met1733Lys missense NM_001407680.1:c.5198T>A NP_001394609.1:p.Met1733Lys missense NM_001407681.1:c.5195T>A NP_001394610.1:p.Met1732Lys missense NM_001407682.1:c.5195T>A NP_001394611.1:p.Met1732Lys missense NM_001407683.1:c.5195T>A NP_001394612.1:p.Met1732Lys missense NM_001407685.1:c.5195T>A NP_001394614.1:p.Met1732Lys missense NM_001407686.1:c.5195T>A NP_001394615.1:p.Met1732Lys missense NM_001407687.1:c.5195T>A NP_001394616.1:p.Met1732Lys missense NM_001407688.1:c.5195T>A NP_001394617.1:p.Met1732Lys missense NM_001407689.1:c.5195T>A NP_001394618.1:p.Met1732Lys missense NM_001407690.1:c.5192T>A NP_001394619.1:p.Met1731Lys missense NM_001407691.1:c.5192T>A NP_001394620.1:p.Met1731Lys missense NM_001407692.1:c.5183T>A NP_001394621.1:p.Met1728Lys missense NM_001407694.1:c.5183T>A NP_001394623.1:p.Met1728Lys missense NM_001407695.1:c.5183T>A NP_001394624.1:p.Met1728Lys missense NM_001407696.1:c.5183T>A NP_001394625.1:p.Met1728Lys missense NM_001407697.1:c.5183T>A NP_001394626.1:p.Met1728Lys missense NM_001407698.1:c.5183T>A NP_001394627.1:p.Met1728Lys missense NM_001407724.1:c.5183T>A NP_001394653.1:p.Met1728Lys missense NM_001407725.1:c.5183T>A NP_001394654.1:p.Met1728Lys missense NM_001407726.1:c.5183T>A NP_001394655.1:p.Met1728Lys missense NM_001407727.1:c.5183T>A NP_001394656.1:p.Met1728Lys missense NM_001407728.1:c.5183T>A NP_001394657.1:p.Met1728Lys missense NM_001407729.1:c.5183T>A NP_001394658.1:p.Met1728Lys missense NM_001407730.1:c.5183T>A NP_001394659.1:p.Met1728Lys missense NM_001407731.1:c.5183T>A NP_001394660.1:p.Met1728Lys missense NM_001407732.1:c.5180T>A NP_001394661.1:p.Met1727Lys missense NM_001407733.1:c.5180T>A NP_001394662.1:p.Met1727Lys missense NM_001407734.1:c.5180T>A NP_001394663.1:p.Met1727Lys missense NM_001407735.1:c.5180T>A NP_001394664.1:p.Met1727Lys missense NM_001407736.1:c.5180T>A NP_001394665.1:p.Met1727Lys missense NM_001407737.1:c.5180T>A NP_001394666.1:p.Met1727Lys missense NM_001407738.1:c.5180T>A NP_001394667.1:p.Met1727Lys missense NM_001407739.1:c.5180T>A NP_001394668.1:p.Met1727Lys missense NM_001407740.1:c.5180T>A NP_001394669.1:p.Met1727Lys missense NM_001407741.1:c.5180T>A NP_001394670.1:p.Met1727Lys missense NM_001407742.1:c.5180T>A NP_001394671.1:p.Met1727Lys missense NM_001407743.1:c.5180T>A NP_001394672.1:p.Met1727Lys missense NM_001407744.1:c.5180T>A NP_001394673.1:p.Met1727Lys missense NM_001407745.1:c.5180T>A NP_001394674.1:p.Met1727Lys missense NM_001407746.1:c.5180T>A NP_001394675.1:p.Met1727Lys missense NM_001407747.1:c.5180T>A NP_001394676.1:p.Met1727Lys missense NM_001407748.1:c.5180T>A NP_001394677.1:p.Met1727Lys missense NM_001407749.1:c.5180T>A NP_001394678.1:p.Met1727Lys missense NM_001407750.1:c.5180T>A NP_001394679.1:p.Met1727Lys missense NM_001407751.1:c.5180T>A NP_001394680.1:p.Met1727Lys missense NM_001407752.1:c.5180T>A NP_001394681.1:p.Met1727Lys missense NM_001407838.1:c.5177T>A NP_001394767.1:p.Met1726Lys missense NM_001407839.1:c.5177T>A NP_001394768.1:p.Met1726Lys missense NM_001407841.1:c.5177T>A NP_001394770.1:p.Met1726Lys missense NM_001407842.1:c.5177T>A NP_001394771.1:p.Met1726Lys missense NM_001407843.1:c.5177T>A NP_001394772.1:p.Met1726Lys missense NM_001407844.1:c.5177T>A NP_001394773.1:p.Met1726Lys missense NM_001407845.1:c.5177T>A NP_001394774.1:p.Met1726Lys missense NM_001407846.1:c.5177T>A NP_001394775.1:p.Met1726Lys missense NM_001407847.1:c.5177T>A NP_001394776.1:p.Met1726Lys missense NM_001407848.1:c.5177T>A NP_001394777.1:p.Met1726Lys missense NM_001407849.1:c.5177T>A NP_001394778.1:p.Met1726Lys missense NM_001407850.1:c.5177T>A NP_001394779.1:p.Met1726Lys missense NM_001407851.1:c.5177T>A NP_001394780.1:p.Met1726Lys missense NM_001407852.1:c.5177T>A NP_001394781.1:p.Met1726Lys missense NM_001407853.1:c.5177T>A NP_001394782.1:p.Met1726Lys missense NM_001407854.1:c.5324T>A NP_001394783.1:p.Met1775Lys missense NM_001407858.1:c.5321T>A NP_001394787.1:p.Met1774Lys missense NM_001407859.1:c.5321T>A NP_001394788.1:p.Met1774Lys missense NM_001407860.1:c.5321T>A NP_001394789.1:p.Met1774Lys missense NM_001407861.1:c.5318T>A NP_001394790.1:p.Met1773Lys missense NM_001407862.1:c.5123T>A NP_001394791.1:p.Met1708Lys missense NM_001407863.1:c.5120T>A NP_001394792.1:p.Met1707Lys missense NM_001407874.1:c.5117T>A NP_001394803.1:p.Met1706Lys missense NM_001407875.1:c.5117T>A NP_001394804.1:p.Met1706Lys missense NM_001407879.1:c.5114T>A NP_001394808.1:p.Met1705Lys missense NM_001407881.1:c.5114T>A NP_001394810.1:p.Met1705Lys missense NM_001407882.1:c.5114T>A NP_001394811.1:p.Met1705Lys missense NM_001407884.1:c.5114T>A NP_001394813.1:p.Met1705Lys missense NM_001407885.1:c.5114T>A NP_001394814.1:p.Met1705Lys missense NM_001407886.1:c.5114T>A NP_001394815.1:p.Met1705Lys missense NM_001407887.1:c.5114T>A NP_001394816.1:p.Met1705Lys missense NM_001407889.1:c.5114T>A NP_001394818.1:p.Met1705Lys missense NM_001407894.1:c.5111T>A NP_001394823.1:p.Met1704Lys missense NM_001407895.1:c.5111T>A NP_001394824.1:p.Met1704Lys missense NM_001407896.1:c.5111T>A NP_001394825.1:p.Met1704Lys missense NM_001407897.1:c.5111T>A NP_001394826.1:p.Met1704Lys missense NM_001407898.1:c.5111T>A NP_001394827.1:p.Met1704Lys missense NM_001407899.1:c.5111T>A NP_001394828.1:p.Met1704Lys missense NM_001407900.1:c.5111T>A NP_001394829.1:p.Met1704Lys missense NM_001407902.1:c.5111T>A NP_001394831.1:p.Met1704Lys missense NM_001407904.1:c.5111T>A NP_001394833.1:p.Met1704Lys missense NM_001407906.1:c.5111T>A NP_001394835.1:p.Met1704Lys missense NM_001407907.1:c.5111T>A NP_001394836.1:p.Met1704Lys missense NM_001407908.1:c.5111T>A NP_001394837.1:p.Met1704Lys missense NM_001407909.1:c.5111T>A NP_001394838.1:p.Met1704Lys missense NM_001407910.1:c.5111T>A NP_001394839.1:p.Met1704Lys missense NM_001407915.1:c.5108T>A NP_001394844.1:p.Met1703Lys missense NM_001407916.1:c.5108T>A NP_001394845.1:p.Met1703Lys missense NM_001407917.1:c.5108T>A NP_001394846.1:p.Met1703Lys missense NM_001407918.1:c.5108T>A NP_001394847.1:p.Met1703Lys missense NM_001407920.1:c.5060T>A NP_001394849.1:p.Met1687Lys missense NM_001407921.1:c.5060T>A NP_001394850.1:p.Met1687Lys missense NM_001407922.1:c.5060T>A NP_001394851.1:p.Met1687Lys missense NM_001407923.1:c.5060T>A NP_001394852.1:p.Met1687Lys missense NM_001407924.1:c.5060T>A NP_001394853.1:p.Met1687Lys missense NM_001407925.1:c.5060T>A NP_001394854.1:p.Met1687Lys missense NM_001407926.1:c.5060T>A NP_001394855.1:p.Met1687Lys missense NM_001407927.1:c.5057T>A NP_001394856.1:p.Met1686Lys missense NM_001407928.1:c.5057T>A NP_001394857.1:p.Met1686Lys missense NM_001407929.1:c.5057T>A NP_001394858.1:p.Met1686Lys missense NM_001407930.1:c.5057T>A NP_001394859.1:p.Met1686Lys missense NM_001407931.1:c.5057T>A NP_001394860.1:p.Met1686Lys missense NM_001407932.1:c.5057T>A NP_001394861.1:p.Met1686Lys missense NM_001407933.1:c.5057T>A NP_001394862.1:p.Met1686Lys missense NM_001407934.1:c.5054T>A NP_001394863.1:p.Met1685Lys missense NM_001407935.1:c.5054T>A NP_001394864.1:p.Met1685Lys missense NM_001407936.1:c.5054T>A NP_001394865.1:p.Met1685Lys missense NM_001407937.1:c.5201T>A NP_001394866.1:p.Met1734Lys missense NM_001407938.1:c.5201T>A NP_001394867.1:p.Met1734Lys missense NM_001407939.1:c.5198T>A NP_001394868.1:p.Met1733Lys missense NM_001407940.1:c.5198T>A NP_001394869.1:p.Met1733Lys missense NM_001407941.1:c.5195T>A NP_001394870.1:p.Met1732Lys missense NM_001407942.1:c.5183T>A NP_001394871.1:p.Met1728Lys missense NM_001407943.1:c.5180T>A NP_001394872.1:p.Met1727Lys missense NM_001407944.1:c.5180T>A NP_001394873.1:p.Met1727Lys missense NM_001407945.1:c.5180T>A NP_001394874.1:p.Met1727Lys missense NM_001407946.1:c.4991T>A NP_001394875.1:p.Met1664Lys missense NM_001407947.1:c.4991T>A NP_001394876.1:p.Met1664Lys missense NM_001407948.1:c.4991T>A NP_001394877.1:p.Met1664Lys missense NM_001407949.1:c.4991T>A NP_001394878.1:p.Met1664Lys missense NM_001407950.1:c.4988T>A NP_001394879.1:p.Met1663Lys missense NM_001407951.1:c.4988T>A NP_001394880.1:p.Met1663Lys missense NM_001407952.1:c.4988T>A NP_001394881.1:p.Met1663Lys missense NM_001407953.1:c.4988T>A NP_001394882.1:p.Met1663Lys missense NM_001407954.1:c.4988T>A NP_001394883.1:p.Met1663Lys missense NM_001407955.1:c.4988T>A NP_001394884.1:p.Met1663Lys missense NM_001407956.1:c.4985T>A NP_001394885.1:p.Met1662Lys missense NM_001407957.1:c.4985T>A NP_001394886.1:p.Met1662Lys missense NM_001407958.1:c.4985T>A NP_001394887.1:p.Met1662Lys missense NM_001407959.1:c.4943T>A NP_001394888.1:p.Met1648Lys missense NM_001407960.1:c.4940T>A NP_001394889.1:p.Met1647Lys missense NM_001407962.1:c.4940T>A NP_001394891.1:p.Met1647Lys missense NM_001407963.1:c.4937T>A NP_001394892.1:p.Met1646Lys missense NM_001407964.1:c.4862T>A NP_001394893.1:p.Met1621Lys missense NM_001407965.1:c.4817T>A NP_001394894.1:p.Met1606Lys missense NM_001407966.1:c.4436T>A NP_001394895.1:p.Met1479Lys missense NM_001407967.1:c.4433T>A NP_001394896.1:p.Met1478Lys missense NM_001407968.1:c.2720T>A NP_001394897.1:p.Met907Lys missense NM_001407969.1:c.2717T>A NP_001394898.1:p.Met906Lys missense NM_001407970.1:c.2081T>A NP_001394899.1:p.Met694Lys missense NM_001407971.1:c.2081T>A NP_001394900.1:p.Met694Lys missense NM_001407972.1:c.2078T>A NP_001394901.1:p.Met693Lys missense NM_001407973.1:c.2015T>A NP_001394902.1:p.Met672Lys missense NM_001407974.1:c.2015T>A NP_001394903.1:p.Met672Lys missense NM_001407975.1:c.2015T>A NP_001394904.1:p.Met672Lys missense NM_001407976.1:c.2015T>A NP_001394905.1:p.Met672Lys missense NM_001407977.1:c.2015T>A NP_001394906.1:p.Met672Lys missense NM_001407978.1:c.2015T>A NP_001394907.1:p.Met672Lys missense NM_001407979.1:c.2012T>A NP_001394908.1:p.Met671Lys missense NM_001407980.1:c.2012T>A NP_001394909.1:p.Met671Lys missense NM_001407981.1:c.2012T>A NP_001394910.1:p.Met671Lys missense NM_001407982.1:c.2012T>A NP_001394911.1:p.Met671Lys missense NM_001407983.1:c.2012T>A NP_001394912.1:p.Met671Lys missense NM_001407984.1:c.2012T>A NP_001394913.1:p.Met671Lys missense NM_001407985.1:c.2012T>A NP_001394914.1:p.Met671Lys missense NM_001407986.1:c.2012T>A NP_001394915.1:p.Met671Lys missense NM_001407990.1:c.2012T>A NP_001394919.1:p.Met671Lys missense NM_001407991.1:c.2012T>A NP_001394920.1:p.Met671Lys missense NM_001407992.1:c.2012T>A NP_001394921.1:p.Met671Lys missense NM_001407993.1:c.2012T>A NP_001394922.1:p.Met671Lys missense NM_001408392.1:c.2009T>A NP_001395321.1:p.Met670Lys missense NM_001408396.1:c.2009T>A NP_001395325.1:p.Met670Lys missense NM_001408397.1:c.2009T>A NP_001395326.1:p.Met670Lys missense NM_001408398.1:c.2009T>A NP_001395327.1:p.Met670Lys missense NM_001408399.1:c.2009T>A NP_001395328.1:p.Met670Lys missense NM_001408400.1:c.2009T>A NP_001395329.1:p.Met670Lys missense NM_001408401.1:c.2009T>A NP_001395330.1:p.Met670Lys missense NM_001408402.1:c.2009T>A NP_001395331.1:p.Met670Lys missense NM_001408403.1:c.2009T>A NP_001395332.1:p.Met670Lys missense NM_001408404.1:c.2009T>A NP_001395333.1:p.Met670Lys missense NM_001408406.1:c.2006T>A NP_001395335.1:p.Met669Lys missense NM_001408407.1:c.2006T>A NP_001395336.1:p.Met669Lys missense NM_001408408.1:c.2006T>A NP_001395337.1:p.Met669Lys missense NM_001408409.1:c.2003T>A NP_001395338.1:p.Met668Lys missense NM_001408410.1:c.1940T>A NP_001395339.1:p.Met647Lys missense NM_001408411.1:c.1937T>A NP_001395340.1:p.Met646Lys missense NM_001408412.1:c.1934T>A NP_001395341.1:p.Met645Lys missense NM_001408413.1:c.1934T>A NP_001395342.1:p.Met645Lys missense NM_001408414.1:c.1934T>A NP_001395343.1:p.Met645Lys missense NM_001408415.1:c.1934T>A NP_001395344.1:p.Met645Lys missense NM_001408416.1:c.1934T>A NP_001395345.1:p.Met645Lys missense NM_001408418.1:c.1898T>A NP_001395347.1:p.Met633Lys missense NM_001408419.1:c.1898T>A NP_001395348.1:p.Met633Lys missense NM_001408420.1:c.1898T>A NP_001395349.1:p.Met633Lys missense NM_001408421.1:c.1895T>A NP_001395350.1:p.Met632Lys missense NM_001408422.1:c.1895T>A NP_001395351.1:p.Met632Lys missense NM_001408423.1:c.1895T>A NP_001395352.1:p.Met632Lys missense NM_001408424.1:c.1895T>A NP_001395353.1:p.Met632Lys missense NM_001408425.1:c.1892T>A NP_001395354.1:p.Met631Lys missense NM_001408426.1:c.1892T>A NP_001395355.1:p.Met631Lys missense NM_001408427.1:c.1892T>A NP_001395356.1:p.Met631Lys missense NM_001408428.1:c.1892T>A NP_001395357.1:p.Met631Lys missense NM_001408429.1:c.1892T>A NP_001395358.1:p.Met631Lys missense NM_001408430.1:c.1892T>A NP_001395359.1:p.Met631Lys missense NM_001408431.1:c.1892T>A NP_001395360.1:p.Met631Lys missense NM_001408432.1:c.1889T>A NP_001395361.1:p.Met630Lys missense NM_001408433.1:c.1889T>A NP_001395362.1:p.Met630Lys missense NM_001408434.1:c.1889T>A NP_001395363.1:p.Met630Lys missense NM_001408435.1:c.1889T>A NP_001395364.1:p.Met630Lys missense NM_001408436.1:c.1889T>A NP_001395365.1:p.Met630Lys missense NM_001408437.1:c.1889T>A NP_001395366.1:p.Met630Lys missense NM_001408438.1:c.1889T>A NP_001395367.1:p.Met630Lys missense NM_001408439.1:c.1889T>A NP_001395368.1:p.Met630Lys missense NM_001408440.1:c.1889T>A NP_001395369.1:p.Met630Lys missense NM_001408441.1:c.1889T>A NP_001395370.1:p.Met630Lys missense NM_001408442.1:c.1889T>A NP_001395371.1:p.Met630Lys missense NM_001408443.1:c.1889T>A NP_001395372.1:p.Met630Lys missense NM_001408444.1:c.1889T>A NP_001395373.1:p.Met630Lys missense NM_001408445.1:c.1886T>A NP_001395374.1:p.Met629Lys missense NM_001408446.1:c.1886T>A NP_001395375.1:p.Met629Lys missense NM_001408447.1:c.1886T>A NP_001395376.1:p.Met629Lys missense NM_001408448.1:c.1886T>A NP_001395377.1:p.Met629Lys missense NM_001408450.1:c.1886T>A NP_001395379.1:p.Met629Lys missense NM_001408451.1:c.1880T>A NP_001395380.1:p.Met627Lys missense NM_001408452.1:c.1874T>A NP_001395381.1:p.Met625Lys missense NM_001408453.1:c.1874T>A NP_001395382.1:p.Met625Lys missense NM_001408454.1:c.1874T>A NP_001395383.1:p.Met625Lys missense NM_001408455.1:c.1874T>A NP_001395384.1:p.Met625Lys missense NM_001408456.1:c.1874T>A NP_001395385.1:p.Met625Lys missense NM_001408457.1:c.1874T>A NP_001395386.1:p.Met625Lys missense NM_001408458.1:c.1871T>A NP_001395387.1:p.Met624Lys missense NM_001408459.1:c.1871T>A NP_001395388.1:p.Met624Lys missense NM_001408460.1:c.1871T>A NP_001395389.1:p.Met624Lys missense NM_001408461.1:c.1871T>A NP_001395390.1:p.Met624Lys missense NM_001408462.1:c.1871T>A NP_001395391.1:p.Met624Lys missense NM_001408463.1:c.1871T>A NP_001395392.1:p.Met624Lys missense NM_001408464.1:c.1871T>A NP_001395393.1:p.Met624Lys missense NM_001408465.1:c.1871T>A NP_001395394.1:p.Met624Lys missense NM_001408466.1:c.1871T>A NP_001395395.1:p.Met624Lys missense NM_001408467.1:c.1871T>A NP_001395396.1:p.Met624Lys missense NM_001408468.1:c.1868T>A NP_001395397.1:p.Met623Lys missense NM_001408469.1:c.1868T>A NP_001395398.1:p.Met623Lys missense NM_001408470.1:c.1868T>A NP_001395399.1:p.Met623Lys missense NM_001408472.1:c.2012T>A NP_001395401.1:p.Met671Lys missense NM_001408473.1:c.2009T>A NP_001395402.1:p.Met670Lys missense NM_001408474.1:c.1814T>A NP_001395403.1:p.Met605Lys missense NM_001408475.1:c.1811T>A NP_001395404.1:p.Met604Lys missense NM_001408476.1:c.1811T>A NP_001395405.1:p.Met604Lys missense NM_001408478.1:c.1805T>A NP_001395407.1:p.Met602Lys missense NM_001408479.1:c.1805T>A NP_001395408.1:p.Met602Lys missense NM_001408480.1:c.1805T>A NP_001395409.1:p.Met602Lys missense NM_001408481.1:c.1802T>A NP_001395410.1:p.Met601Lys missense NM_001408482.1:c.1802T>A NP_001395411.1:p.Met601Lys missense NM_001408483.1:c.1802T>A NP_001395412.1:p.Met601Lys missense NM_001408484.1:c.1802T>A NP_001395413.1:p.Met601Lys missense NM_001408485.1:c.1802T>A NP_001395414.1:p.Met601Lys missense NM_001408489.1:c.1802T>A NP_001395418.1:p.Met601Lys missense NM_001408490.1:c.1802T>A NP_001395419.1:p.Met601Lys missense NM_001408491.1:c.1802T>A NP_001395420.1:p.Met601Lys missense NM_001408492.1:c.1799T>A NP_001395421.1:p.Met600Lys missense NM_001408493.1:c.1799T>A NP_001395422.1:p.Met600Lys missense NM_001408494.1:c.1775T>A NP_001395423.1:p.Met592Lys missense NM_001408495.1:c.1769T>A NP_001395424.1:p.Met590Lys missense NM_001408496.1:c.1751T>A NP_001395425.1:p.Met584Lys missense NM_001408497.1:c.1751T>A NP_001395426.1:p.Met584Lys missense NM_001408498.1:c.1751T>A NP_001395427.1:p.Met584Lys missense NM_001408499.1:c.1751T>A NP_001395428.1:p.Met584Lys missense NM_001408500.1:c.1751T>A NP_001395429.1:p.Met584Lys missense NM_001408501.1:c.1751T>A NP_001395430.1:p.Met584Lys missense NM_001408502.1:c.1748T>A NP_001395431.1:p.Met583Lys missense NM_001408503.1:c.1748T>A NP_001395432.1:p.Met583Lys missense NM_001408504.1:c.1748T>A NP_001395433.1:p.Met583Lys missense NM_001408505.1:c.1745T>A NP_001395434.1:p.Met582Lys missense NM_001408506.1:c.1688T>A NP_001395435.1:p.Met563Lys missense NM_001408507.1:c.1685T>A NP_001395436.1:p.Met562Lys missense NM_001408508.1:c.1676T>A NP_001395437.1:p.Met559Lys missense NM_001408509.1:c.1673T>A NP_001395438.1:p.Met558Lys missense NM_001408510.1:c.1634T>A NP_001395439.1:p.Met545Lys missense NM_001408511.1:c.1631T>A NP_001395440.1:p.Met544Lys missense NM_001408512.1:c.1511T>A NP_001395441.1:p.Met504Lys missense NM_001408513.1:c.1484T>A NP_001395442.1:p.Met495Lys missense NM_001408514.1:c.1088T>A NP_001395443.1:p.Met363Lys missense NM_007297.4:c.5183T>A NP_009228.2:p.Met1728Lys missense NM_007298.4:c.2012T>A NP_009229.2:p.Met671Lys missense NM_007299.4:c.2012T>A NP_009230.2:p.Met671Lys missense NM_007300.4:c.5387T>A NP_009231.2:p.Met1796Lys missense NM_007304.2:c.2012T>A NP_009235.2:p.Met671Lys missense NR_027676.2:n.5501T>A non-coding transcript variant NC_000017.11:g.43051071A>T NC_000017.10:g.41203088A>T NG_005905.2:g.166913T>A LRG_292:g.166913T>A LRG_292t1:c.5324T>A LRG_292p1:p.Met1775Lys P38398:p.Met1775Lys - Protein change
- M1775K, M1728K, M671K, M1796K, M1479K, M1647K, M1685K, M1704K, M1756K, M363K, M544K, M562K, M582K, M625K, M627K, M630K, M668K, M694K, M907K, M1664K, M1686K, M1726K, M1731K, M1732K, M1733K, M1771K, M1773K, M504K, M545K, M592K, M601K, M906K, M1606K, M1646K, M1648K, M1663K, M1687K, M1706K, M1708K, M1727K, M1734K, M1748K, M1755K, M1795K, M495K, M558K, M559K, M563K, M583K, M602K, M604K, M624K, M647K, M669K, M670K, M693K, M1478K, M1621K, M1662K, M1703K, M1705K, M1707K, M1747K, M1749K, M1770K, M1772K, M1774K, M1797K, M584K, M590K, M600K, M605K, M623K, M629K, M631K, M632K, M633K, M645K, M646K, M672K
- Other names
-
5443T>A
- Canonical SPDI
- NC_000017.11:43051070:A:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
functionally_abnormal; Sequence Ontology [ SO:0002218]The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5324T>A, a MISSENSE variant, produced a function score of -1.83, corresponding to a functional classification of LOSS_OF_FUNCTION. SGE function score ranges for classification are as follows: ‘functional’, score > -0.748; ‘intermediate’, -0.748 > score > -1.328; ‘non-functional’, score < -1.328. The median synonymous SNV scored 0.0 and the median nonsense SNV scored -2.12. [submitted by Brotman Baty Institute, University of Washington]
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
13051 | 14858 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (6) |
reviewed by expert panel
|
Aug 10, 2015 | RCV000019265.20 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jan 31, 2014 | RCV000496817.9 | |
| Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 15, 2020 | RCV001526335.12 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Aug 10, 2015)
|
reviewed by expert panel
Method: curation
|
Breast-ovarian cancer, familial 1
Affected status: unknown
Allele origin:
germline
|
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV000244397.1
First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
Comment:
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on … (more)
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 (less)
|
|
|
Pathogenic
(Oct 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000326264.4
First in ClinVar: Sep 29, 2015 Last updated: Dec 11, 2022 |
|
|
|
Likely pathogenic
(Sep 15, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001736649.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Comment:
This missense variant replaces methionine with lysine at codon 1775 in the BRCT2 domain of the BRCA1 protein. Computational prediction suggests that this variant may … (more)
This missense variant replaces methionine with lysine at codon 1775 in the BRCT2 domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein is highly defective for specific phosphopeptide recognition and transcriptional activity (PMID: 18285836, 20516115). This variant has also been reported to cause loss of BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been observed in two individuals affected with familial breast cancer (PMID: 18285836) and reported to be disease-causing based on multifactorial likelihood analyses (PMID: 18285836, 21990134). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Met1775Arg, is a well documented pathogenic mutation (Clinvar variation ID: 17694), indicating that methionine at this position is important for BRCA1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
|
|
|
Pathogenic
(Jun 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556753.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
Comment:
The BRCA1 c.5324T>A variant is classified as Pathogenic (PS3, PM2, PM5, PP3, PP5)
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Likely pathogenic
(Feb 24, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002646820.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.M1775K variant (also known as c.5324T>A), located in coding exon 19 of the BRCA1 gene, results from a T to A substitution at nucleotide … (more)
The p.M1775K variant (also known as c.5324T>A), located in coding exon 19 of the BRCA1 gene, results from a T to A substitution at nucleotide position 5324. The methionine at codon 1775 is replaced by lysine, an amino acid with similar properties. This alteration, as well as a known pathogenic close match alteration BRCA2 p.M1775R, were non-functional in many different assays including a colony size assay, a haploid cell survival assay, multiple transcription activation assays, and multiple protein binding and specificity assays (Thouvenot P et al. PLoS Genet. 2016 06;12:e1006096; Findlay GM et al. Nature. 2018 10;562:217-222; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Tischkowitz M et al. Eur. J. Hum. Genet. 2008 Jul;16:820-32; Drikos I et al. Proteins. 2009 Nov;77:464-76). This alteration was identified in two families in the literature and segregated with disease in both. In one family, this variant was found in cis with BRCA2 p.D1778N, a likely pathogenic splicing alteration (Tischkowitz M et al. Eur. J. Hum. Genet. 2008 Jul;16:820-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic (less)
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Pathogenic
(Jul 01, 2008)
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no assertion criteria provided
Method: literature only
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BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039553.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 29, 2015 |
Comment on evidence:
In 2 unrelated European families with a history of breast cancer (604370), Tischkowitz et al. (2008) identified a met1775-to-lys (M1775K) substitution in the BRCA1 gene … (more)
In 2 unrelated European families with a history of breast cancer (604370), Tischkowitz et al. (2008) identified a met1775-to-lys (M1775K) substitution in the BRCA1 gene and demonstrated its pathogenicity. The authors showed that expression of the M1775K-mutant protein in yeast and mammalian cells resulted in markedly reduced transcriptional activity of BRCA1, indicating the pathogenicity of the variant. The M1775K mutation disrupted the phosphopeptide-binding pocket of the BRCT domains, thereby inhibiting BRCA1 interaction with the proteins BRIP1 (605882) and CTIP (RBBP8; 604128), which are involved in DNA damage-induced checkpoint control. These findings indicated that the BRCT phosphopeptide-binding pocket is critical for the tumor suppression function of BRCA1. Tischkowitz et al. (2008) used a combination of functional, structural, molecular, and evolutionary methods in their study. (less)
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Likely pathogenic
(Jun 21, 2010)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 1
Affected status: not provided
Allele origin:
germline
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Sharing Clinical Reports Project (SCRP)
Accession: SCV000053840.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
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Pathogenic
(Jan 31, 2014)
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no assertion criteria provided
Method: research
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000587494.1 First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017 |
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not provided
(-)
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no classification provided
Method: in vitro
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Breast-ovarian cancer, familial 1
Affected status: not applicable
Allele origin:
not applicable
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Brotman Baty Institute, University of Washington
Accession: SCV001243073.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
Method: saturation genome editing in haploid cells
Result:
LOSS_OF_FUNCTION:-1.83186236584358
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Comment:
Comment:
This missense variant replaces methionine with lysine at codon 1775 in the BRCT2 domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein is highly defective for specific phosphopeptide recognition and transcriptional activity (PMID: 18285836, 20516115). This variant has also been reported to cause loss of BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been observed in two individuals affected with familial breast cancer (PMID: 18285836) and reported to be disease-causing based on multifactorial likelihood analyses (PMID: 18285836, 21990134). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Met1775Arg, is a well documented pathogenic mutation (Clinvar variation ID: 17694), indicating that methionine at this position is important for BRCA1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
The BRCA1 c.5324T>A variant is classified as Pathogenic (PS3, PM2, PM5, PP3, PP5)
Comment:
The p.M1775K variant (also known as c.5324T>A), located in coding exon 19 of the BRCA1 gene, results from a T to A substitution at nucleotide position 5324. The methionine at codon 1775 is replaced by lysine, an amino acid with similar properties. This alteration, as well as a known pathogenic close match alteration BRCA2 p.M1775R, were non-functional in many different assays including a colony size assay, a haploid cell survival assay, multiple transcription activation assays, and multiple protein binding and specificity assays (Thouvenot P et al. PLoS Genet. 2016 06;12:e1006096; Findlay GM et al. Nature. 2018 10;562:217-222; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Tischkowitz M et al. Eur. J. Hum. Genet. 2008 Jul;16:820-32; Drikos I et al. Proteins. 2009 Nov;77:464-76). This alteration was identified in two families in the literature and segregated with disease in both. In one family, this variant was found in cis with BRCA2 p.D1778N, a likely pathogenic splicing alteration (Tischkowitz M et al. Eur. J. Hum. Genet. 2008 Jul;16:820-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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functionally_abnormal
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Method citation(s):
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Brotman Baty Institute, University of Washington
Accession: SCV001243073.1
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Comment:
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5324T>A, a MISSENSE variant, produced a function score of -1.83, corresponding to a functional classification of LOSS_OF_FUNCTION. … (more)
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5324T>A, a MISSENSE variant, produced a function score of -1.83, corresponding to a functional classification of LOSS_OF_FUNCTION. SGE function score ranges for classification are as follows: ‘functional’, score > -0.748; ‘intermediate’, -0.748 > score > -1.328; ‘non-functional’, score < -1.328. The median synonymous SNV scored 0.0 and the median nonsense SNV scored -2.12. (less)
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Comment:
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1
Comment:
This missense variant replaces methionine with lysine at codon 1775 in the BRCT2 domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein is highly defective for specific phosphopeptide recognition and transcriptional activity (PMID: 18285836, 20516115). This variant has also been reported to cause loss of BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been observed in two individuals affected with familial breast cancer (PMID: 18285836) and reported to be disease-causing based on multifactorial likelihood analyses (PMID: 18285836, 21990134). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Met1775Arg, is a well documented pathogenic mutation (Clinvar variation ID: 17694), indicating that methionine at this position is important for BRCA1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
The BRCA1 c.5324T>A variant is classified as Pathogenic (PS3, PM2, PM5, PP3, PP5)
Comment:
The p.M1775K variant (also known as c.5324T>A), located in coding exon 19 of the BRCA1 gene, results from a T to A substitution at nucleotide position 5324. The methionine at codon 1775 is replaced by lysine, an amino acid with similar properties. This alteration, as well as a known pathogenic close match alteration BRCA2 p.M1775R, were non-functional in many different assays including a colony size assay, a haploid cell survival assay, multiple transcription activation assays, and multiple protein binding and specificity assays (Thouvenot P et al. PLoS Genet. 2016 06;12:e1006096; Findlay GM et al. Nature. 2018 10;562:217-222; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Tischkowitz M et al. Eur. J. Hum. Genet. 2008 Jul;16:820-32; Drikos I et al. Proteins. 2009 Nov;77:464-76). This alteration was identified in two families in the literature and segregated with disease in both. In one family, this variant was found in cis with BRCA2 p.D1778N, a likely pathogenic splicing alteration (Tischkowitz M et al. Eur. J. Hum. Genet. 2008 Jul;16:820-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Accurate classification of BRCA1 variants with saturation genome editing. | Findlay GM | Nature | 2018 | PMID: 30209399 |
| Functional Assessment of Genetic Variants with Outcomes Adapted to Clinical Decision-Making. | Thouvenot P | PLoS genetics | 2016 | PMID: 27272900 |
| A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). | Lindor NM | Human mutation | 2012 | PMID: 21990134 |
| Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. | Lee MS | Cancer research | 2010 | PMID: 20516115 |
| Characterization of cancer-linked BRCA1-BRCT missense variants and their interaction with phosphoprotein targets. | Drikos I | Proteins | 2009 | PMID: 19452558 |
| Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket: a multi-modal approach. | Tischkowitz M | European journal of human genetics : EJHG | 2008 | PMID: 18285836 |
| Retroviral mediated transfer and expression of exogenous genes in primary lymphoid cells: assaying for a viral transactivator activity in normal and malignant cells. | Strair RK | Blood | 1990 | PMID: 2144777 |
| http://hci-exlovd.hci.utah.edu/variants.php?select_db=BRCA1&action=search_all&search_Variant%2FDNA=c.5324T%3EA | - | - | - | - |
| https://sge.gs.washington.edu/BRCA1/ | - | - | - | - |
Text-mined citations for rs41293463 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.