ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.1694C>T (p.Ala565Val)
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.
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(10); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000059.4(BRCA2):c.1694C>T (p.Ala565Val)
Variation ID: 182186 Accession: VCV000182186.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q13.1 13: 32333172 (GRCh38) [ NCBI UCSC ] 13: 32907309 (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 Jan 7, 2017 Apr 20, 2024 Jan 21, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000059.4:c.1694C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Ala565Val missense NC_000013.11:g.32333172C>T NC_000013.10:g.32907309C>T NG_012772.3:g.22693C>T LRG_293:g.22693C>T LRG_293t1:c.1694C>T LRG_293p1:p.Ala565Val - Protein change
- A565V
- Other names
- p.A565V:GCC>GTC
- Canonical SPDI
- NC_000013.11:32333171:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00007
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. |
|||
BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18542 | 18699 |
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. |
---|---|---|---|---|
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 21, 2024 | RCV000199884.9 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Apr 26, 2023 | RCV000509822.11 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 16, 2023 | RCV000586436.12 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Aug 7, 2021 | RCV001706064.1 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Aug 31, 2022 | RCV003390857.4 | |
Uncertain significance (1) |
criteria provided, single submitter
|
May 16, 2023 | RCV003998438.1 |
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
(Aug 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694558.2
First in ClinVar: Mar 17, 2018 Last updated: Sep 26, 2021 |
Comment:
Variant summary: BRCA2 c.1694C>T (p.Ala565Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: BRCA2 c.1694C>T (p.Ala565Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251138 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1694C>T has been reported in the literature in at-least two individuals of African origin who were affected with Breast Cancer (example, Fackenthal_2012, Pal_2015), however it was also found in 1/2559 African American women, who are older than 70 years of age, and never had cancer (FLOSSIES database). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
Uncertain significance
(Sep 01, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002533252.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
Uncertain significance
(Nov 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000608233.4
First in ClinVar: Oct 23, 2017 Last updated: Nov 29, 2022 |
Comment:
The p.A565V variant (also known as c.1694C>T), located in coding exon 9 of the BRCA2 gene, results from a C to T substitution at nucleotide … (more)
The p.A565V variant (also known as c.1694C>T), located in coding exon 9 of the BRCA2 gene, results from a C to T substitution at nucleotide position 1694. The alanine at codon 565 is replaced by valine, an amino acid with similar properties. In one study, this alteration was reported in 1/434 Nigerian breast cancer patients unselected for age of onset or family history (Fackenthal JD et al. Int. J. Cancer 2012 Sep; 131(5):1114-23). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
|
|
Uncertain significance
(Jun 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000210276.13
First in ClinVar: Feb 24, 2015 Last updated: Jul 08, 2023 |
Comment:
Identified in individual(s) with breast cancer (Fackenthal et al., 2012; Pal et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In … (more)
Identified in individual(s) with breast cancer (Fackenthal et al., 2012; Pal et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 1922C>T; This variant is associated with the following publications: (PMID: 23891399, 29884841, 32377563, 22034289, 26287763, 31911673, 31853058) (less)
|
|
Uncertain significance
(Aug 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
BRCA2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004119264.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The BRCA2 c.1694C>T variant is predicted to result in the amino acid substitution p.Ala565Val. To our knowledge, this variant has not been reported in the … (more)
The BRCA2 c.1694C>T variant is predicted to result in the amino acid substitution p.Ala565Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as uncertain by multiple submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/182186). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
|
Uncertain significance
(Aug 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001133688.4
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 26287763 (2015), 22034289 (2012)), and described to be located in … (more)
In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 26287763 (2015), 22034289 (2012)), and described to be located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.00017 (7/41412 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
Uncertain significance
(Apr 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000903459.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with valine at codon 565 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces alanine with valine at codon 565 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 22034289). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain significance
(Jan 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000254170.8
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 565 of the BRCA2 protein (p.Ala565Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 565 of the BRCA2 protein (p.Ala565Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 22034289). ClinVar contains an entry for this variant (Variation ID: 182186). 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 BRCA2 protein function with a negative predictive value of 95%. 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
(Dec 15, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000224764.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
Likely benign
(Mar 23, 2023)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV003851576.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
Comment:
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
|
|
Uncertain Significance
(May 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004846948.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces alanine with valine at codon 565 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces alanine with valine at codon 565 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 22034289). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 2
|
|
click to load more click to collapse |
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots". | Dines JN | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31911673 |
A high frequency of BRCA mutations in young black women with breast cancer residing in Florida. | Pal T | Cancer | 2015 | PMID: 26287763 |
High prevalence of BRCA1 and BRCA2 mutations in unselected Nigerian breast cancer patients. | Fackenthal JD | International journal of cancer | 2012 | PMID: 22034289 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA2 | - | - | - | - |
Text-mined citations for rs55821741 ...
HelpRecord last updated Apr 20, 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.