The c.2556_2557delCA variant, located in coding exon 15 of the PMS2 gene, results from a deletion of two nucleotides at nucleotide positions 2556 to 2557 causing a translational frameshift with a predicted alternate stop codon (p.I853Rfs*23). This frameshift occurs at the 3' terminus of PMS2 and results in the elongation of the protein by 23 amino acids. Based on an internal structural analysis, this variant is anticipated to result in a significant decrease in protein stability and protein-protein interaction (Ambry internal data; Gueneau E et al. Nat. Struct. Mol. Biol., 2013 Apr;20:461-8). This variant was also identified in conjunction with a somatic pathogenic PMS2 variant in a proband whose Lynch syndrome associated tumor demonstrated high microsatellite instability (MSI-H) with isolated loss of PMS2 on immunohistochemistry (IHC) and MLH1 promoter hypermethylation was absent (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.2556_2557del (p.Ile853fs)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(1)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Likely pathogenic
1
criteria provided, single submitter
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000535.7(PMS2):c.2556_2557del (p.Ile853fs)
Variation ID: 1793011 Accession: VCV001793011.2
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 7p22.1 7: 5973431-5973432 (GRCh38) [ NCBI UCSC ] 7: 6013062-6013063 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Nov 29, 2022 May 1, 2024 Oct 22, 2020 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000535.7:c.2556_2557del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Ile853fs frameshift NM_000535.5:c.2553_2554AC[1] NP_000526.1:p.Ile853Argfs frameshift NM_000535.5:c.2556_2557delCA frameshift NM_001018040.1:c.2148_2149AC[1] NP_001018050.1:p.Ile718Argfs frameshift NM_001322003.2:c.2151_2152del NP_001308932.1:p.Ile718fs frameshift NM_001322004.2:c.2151_2152del NP_001308933.1:p.Ile718fs frameshift NM_001322005.2:c.2151_2152del NP_001308934.1:p.Ile718fs frameshift NM_001322006.2:c.2400_2401del NP_001308935.1:p.Ile801fs frameshift NM_001322007.2:c.2238_2239del NP_001308936.1:p.Ile747fs frameshift NM_001322008.2:c.2238_2239del NP_001308937.1:p.Ile747fs frameshift NM_001322009.2:c.2184_2185del NP_001308938.1:p.Ile729fs frameshift NM_001322010.2:c.1995_1996del NP_001308939.1:p.Ile666fs frameshift NM_001322011.2:c.1623_1624del NP_001308940.1:p.Ile542fs frameshift NM_001322012.2:c.1623_1624del NP_001308941.1:p.Ile542fs frameshift NM_001322013.2:c.1983_1984del NP_001308942.1:p.Ile662fs frameshift NM_001322014.2:c.2589_2590del NP_001308943.1:p.Ile864fs frameshift NM_001322015.2:c.2247_2248del NP_001308944.1:p.Ile750fs frameshift NM_001406866.1:c.2739_2740AC[1] NP_001393795.1:p.Ile915Argfs frameshift NM_001406868.1:c.2577_2578AC[1] NP_001393797.1:p.Ile861Argfs frameshift NM_001406869.1:c.2445_2446AC[1] NP_001393798.1:p.Ile817Argfs frameshift NM_001406870.1:c.2430_2431AC[1] NP_001393799.1:p.Ile812Argfs frameshift NM_001406871.1:c.2409_2410AC[1] NP_001393800.1:p.Ile805Argfs frameshift NM_001406872.1:c.2385_2386AC[1] NP_001393801.1:p.Ile797Argfs frameshift NM_001406873.1:c.2355_2356AC[1] NP_001393802.1:p.Ile787Argfs frameshift NM_001406874.1:c.2385_2386AC[1] NP_001393803.1:p.Ile797Argfs frameshift NM_001406875.1:c.2277_2278AC[1] NP_001393804.1:p.Ile761Argfs frameshift NM_001406876.1:c.2268_2269AC[1] NP_001393805.1:p.Ile758Argfs frameshift NM_001406877.1:c.2244_2245AC[1] NP_001393806.1:p.Ile750Argfs frameshift NM_001406878.1:c.2244_2245AC[1] NP_001393807.1:p.Ile750Argfs frameshift NM_001406879.1:c.2244_2245AC[1] NP_001393808.1:p.Ile750Argfs frameshift NM_001406880.1:c.2244_2245AC[1] NP_001393809.1:p.Ile750Argfs frameshift NM_001406881.1:c.2244_2245AC[1] NP_001393810.1:p.Ile750Argfs frameshift NM_001406882.1:c.2244_2245AC[1] NP_001393811.1:p.Ile750Argfs frameshift NM_001406883.1:c.2235_2236AC[1] NP_001393812.1:p.Ile747Argfs frameshift NM_001406884.1:c.2229_2230AC[1] NP_001393813.1:p.Ile745Argfs frameshift NM_001406885.1:c.2217_2218AC[1] NP_001393814.1:p.Ile741Argfs frameshift NM_001406886.1:c.2187_2188AC[1] NP_001393815.1:p.Ile731Argfs frameshift NM_001406887.1:c.2181_2182AC[1] NP_001393816.1:p.Ile729Argfs frameshift NM_001406888.1:c.2181_2182AC[1] NP_001393817.1:p.Ile729Argfs frameshift NM_001406889.1:c.2148_2149AC[1] NP_001393818.1:p.Ile718Argfs frameshift NM_001406890.1:c.2148_2149AC[1] NP_001393819.1:p.Ile718Argfs frameshift NM_001406891.1:c.2148_2149AC[1] NP_001393820.1:p.Ile718Argfs frameshift NM_001406892.1:c.2148_2149AC[1] NP_001393821.1:p.Ile718Argfs frameshift NM_001406893.1:c.2148_2149AC[1] NP_001393822.1:p.Ile718Argfs frameshift NM_001406894.1:c.2148_2149AC[1] NP_001393823.1:p.Ile718Argfs frameshift NM_001406895.1:c.2148_2149AC[1] NP_001393824.1:p.Ile718Argfs frameshift NM_001406896.1:c.2148_2149AC[1] NP_001393825.1:p.Ile718Argfs frameshift NM_001406897.1:c.2148_2149AC[1] NP_001393826.1:p.Ile718Argfs frameshift NM_001406898.1:c.2148_2149AC[1] NP_001393827.1:p.Ile718Argfs frameshift NM_001406899.1:c.2148_2149AC[1] NP_001393828.1:p.Ile718Argfs frameshift NM_001406900.1:c.2088_2089AC[1] NP_001393829.1:p.Ile698Argfs frameshift NM_001406901.1:c.2079_2080AC[1] NP_001393830.1:p.Ile695Argfs frameshift NM_001406902.1:c.2079_2080AC[1] NP_001393831.1:p.Ile695Argfs frameshift NM_001406903.1:c.2067_2068AC[1] NP_001393832.1:p.Ile691Argfs frameshift NM_001406904.1:c.2040_2041AC[1] NP_001393833.1:p.Ile682Argfs frameshift NM_001406905.1:c.2040_2041AC[1] NP_001393834.1:p.Ile682Argfs frameshift NM_001406906.1:c.1992_1993AC[1] NP_001393835.1:p.Ile666Argfs frameshift NM_001406907.1:c.1992_1993AC[1] NP_001393836.1:p.Ile666Argfs frameshift NM_001406908.1:c.1980_1981AC[1] NP_001393837.1:p.Ile662Argfs frameshift NM_001406909.1:c.1980_1981AC[1] NP_001393838.1:p.Ile662Argfs frameshift NM_001406910.1:c.1836_1837AC[1] NP_001393839.1:p.Ile614Argfs frameshift NM_001406911.1:c.1782_1783AC[1] NP_001393840.1:p.Ile596Argfs frameshift NM_001406912.1:c.1350_1351AC[1] NP_001393841.1:p.Ile452Argfs frameshift NR_003085.2:n.2635_2636AC[1] NR_136154.1:n.2598CA[1] non-coding transcript variant NC_000007.14:g.5973432GT[1] NC_000007.13:g.6013063GT[1] NG_008466.1:g.40673CA[1] LRG_161:g.40673CA[1] LRG_161t1:c.2553_2554AC[1] LRG_161p1:p.Ile853Argfs - Protein change
- I747fs, I750fs, I864fs, I729fs, I662fs, I666fs, I718fs, I801fs, I853fs, I542fs
- Other names
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- Canonical SPDI
- NC_000007.14:5973430:TGTGT:TGT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- 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. |
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| PMS2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5326 | 5429 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 22, 2020 | RCV002433338.2 |
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. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Oct 22, 2020)
|
criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002741128.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.2556_2557delCA variant, located in coding exon 15 of the PMS2 gene, results from a deletion of two nucleotides at nucleotide positions 2556 to 2557 … (more)
The c.2556_2557delCA variant, located in coding exon 15 of the PMS2 gene, results from a deletion of two nucleotides at nucleotide positions 2556 to 2557 causing a translational frameshift with a predicted alternate stop codon (p.I853Rfs*23). This frameshift occurs at the 3' terminus of PMS2 and results in the elongation of the protein by 23 amino acids. Based on an internal structural analysis, this variant is anticipated to result in a significant decrease in protein stability and protein-protein interaction (Ambry internal data; Gueneau E et al. Nat. Struct. Mol. Biol., 2013 Apr;20:461-8). This variant was also identified in conjunction with a somatic pathogenic PMS2 variant in a proband whose Lynch syndrome associated tumor demonstrated high microsatellite instability (MSI-H) with isolated loss of PMS2 on immunohistochemistry (IHC) and MLH1 promoter hypermethylation was absent (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
Comment:
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The c.2556_2557delCA variant, located in coding exon 15 of the PMS2 gene, results from a deletion of two nucleotides at nucleotide positions 2556 to 2557 causing a translational frameshift with a predicted alternate stop codon (p.I853Rfs*23). This frameshift occurs at the 3' terminus of PMS2 and results in the elongation of the protein by 23 amino acids. Based on an internal structural analysis, this variant is anticipated to result in a significant decrease in protein stability and protein-protein interaction (Ambry internal data; Gueneau E et al. Nat. Struct. Mol. Biol., 2013 Apr;20:461-8). This variant was also identified in conjunction with a somatic pathogenic PMS2 variant in a proband whose Lynch syndrome associated tumor demonstrated high microsatellite instability (MSI-H) with isolated loss of PMS2 on immunohistochemistry (IHC) and MLH1 promoter hypermethylation was absent (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 |
|---|---|---|---|---|
| Structure of the MutLα C-terminal domain reveals how Mlh1 contributes to Pms1 endonuclease site. | Gueneau E | Nature structural & molecular biology | 2013 | PMID: 23435383 |
Text-mined citations for this variant ...
HelpRecord last updated May 01, 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.