VCV000187314.18 - ClinVar

NM_002878.4(RAD51D):c.550G>A (p.Glu184Lys)

Germline

Classification

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.

(7)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002878.4(RAD51D):c.550G>A (p.Glu184Lys)

Variation ID: 187314 Accession: VCV000187314.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q12 17: 35106412 (GRCh38) [ NCBI UCSC ] 17: 33433431 (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 30, 2017	Jun 17, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002878.4:c.550G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002869.3:p.Glu184Lys	missense
NM_001142571.2:c.610G>A	NP_001136043.1:p.Glu204Lys	missense
NM_133629.2:c.214G>A
NM_133629.3:c.214G>A	NP_598332.1:p.Glu72Lys	missense
NR_037711.2:n.576G>A		non-coding transcript variant
NR_037712.2:n.441G>A		non-coding transcript variant
NR_037714.1:n.302G>A		non-coding transcript variant
NC_000017.11:g.35106412C>T
NC_000017.10:g.33433431C>T
NG_031858.1:g.18458G>A
LRG_516:g.18458G>A
LRG_516t1:c.550G>A	LRG_516p1:p.Glu184Lys

... more HGVS ... less HGVS

Protein change

E184K, E204K, E72K

Other names

Canonical SPDI

NC_000017.11:35106411:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00040 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Exome Aggregation Consortium (ExAC) 0.00004

1000 Genomes Project 30x 0.00031

1000 Genomes Project 0.00040

Links

ClinGen: CA197328 dbSNP: rs200009601 VarSome

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
Gene	OMIM	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.
RAD51D		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	34	1821
RAD51L3-RFFL	-	-	-	GRCh38	-	1800

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.
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 14, 2022	RCV000167033.9
Breast-ovarian cancer, familial, susceptibility to, 4	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000538714.11
not specified	Uncertain significance (1)	criteria provided, single submitter	Dec 28, 2016	RCV000507856.2
not provided	Uncertain significance (1)	criteria provided, single submitter	Oct 12, 2022	RCV002291584.2

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.
Uncertain significance (Apr 03, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000686467.3 First in ClinVar: Feb 19, 2018 Last updated: Mar 25, 2020
Uncertain significance (Dec 28, 2016)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000602161.2 First in ClinVar: Sep 30, 2017 Last updated: Jan 01, 2022
Uncertain significance (Oct 06, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 4 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000651757.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 184 of the RAD51D protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 184 of the RAD51D protein (p.Glu184Lys). This variant is present in population databases (rs200009601, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 187314). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51D protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Oct 12, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002584126.2 First in ClinVar: Oct 22, 2022 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Chen et al., 2020); This variant is associated with the following publications: (PMID: 32091409, 21111057, 14704354) (less)
Uncertain significance (Jan 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 4 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004239134.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Comment: This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 72 of the RAD51D protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 72 of the RAD51D protein (p.Glu72Lys). This variant is present in population databases (rs200009601, gnomAD 0.02%). This variant observed in individuals with breast cancer (Chen et al., 2020); This variant is associated with the following publications: (PMID: 32091409, 21111057, 14704354) . ClinVar contains an entry for this variant (Variation ID: 187314) classified as uncertain significant . This amino acid position is poorly conserved (PhyloP=2.7) .In addition, this alteration is predicted to be tolerated by in silico analysis. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less) Zygosity: Single Heterozygote Age: 60-69 years Sex: female
Uncertain significance (Dec 14, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000217856.8 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Comment: The p.E184K variant (also known as c.550G>A), located in coding exon 6 of the RAD51D gene, results from a G to A substitution at nucleotide … (more) The p.E184K variant (also known as c.550G>A), located in coding exon 6 of the RAD51D gene, results from a G to A substitution at nucleotide position 550. The glutamic acid at codon 184 is replaced by lysine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Jan 03, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 4 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005054027.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 184 of the RAD51D protein (p.Glu184Lys). This variant is present in population databases (rs200009601, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 187314). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51D protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Chen et al., 2020); This variant is associated with the following publications: (PMID: 32091409, 21111057, 14704354)

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 72 of the RAD51D protein (p.Glu72Lys). This variant is present in population databases (rs200009601, gnomAD 0.02%). This variant observed in individuals with breast cancer (Chen et al., 2020); This variant is associated with the following publications: (PMID: 32091409, 21111057, 14704354) . ClinVar contains an entry for this variant (Variation ID: 187314) classified as uncertain significant . This amino acid position is poorly conserved (PhyloP=2.7) .In addition, this alteration is predicted to be tolerated by in silico analysis. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The p.E184K variant (also known as c.550G>A), located in coding exon 6 of the RAD51D gene, results from a G to A substitution at nucleotide position 550. The glutamic acid at codon 184 is replaced by lysine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs200009601 ...

These 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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_002878.4(RAD51D):c.550G>A (p.Glu184Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs200009601 ...