Submissions for variant NM_000059.4(BRCA2):c.6176G>A (p.Ser2059Asn)

gnomAD frequency: 0.00002  dbSNP: rs587780657

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122921	SCV000166179	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-12	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 2059 of the BRCA2 protein (p.Ser2059Asn). This variant is present in population databases (rs587780657, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 24504028, 28503720). ClinVar contains an entry for this variant (Variation ID: 135808). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV000131374	SCV000186350	likely benign	Hereditary cancer-predisposing syndrome	2024-05-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003441746	SCV000296548	uncertain significance	not provided	2023-06-20	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 28503720 (2017)) and ovarian cancer (PMID: 24504028 (2014)). The frequency of this variant in the general population, 0.000004 (1/250662 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.
Color Diagnostics, LLC DBA Color Health	RCV000131374	SCV000906131	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-22	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 2059 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 reported for this variant. This variant has been reported in one individual each affected with breast and ovarian cancer (PMID: 24504028, 28503720). This variant has been identified in 1/250662 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228445	SCV002511881	uncertain significance	not specified	2022-04-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6176G>A (p.Ser2059Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250662 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6176G>A has been reported in the literature as a VUS in individuals affected with epithelial ovarian cancer (example, Cunningham_2014) and invasive breast cancer (example, Rummel_2017). 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. Four 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131374	SCV003852295	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
GeneDx	RCV003441746	SCV004169054	uncertain significance	not provided	2023-11-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 6404G>A; This variant is associated with the following publications: (PMID: 24504028, 28503720, 26295337, 9002670, 22193408, 32377563, 31853058, 29884841)
All of Us Research Program, National Institutes of Health	RCV004804122	SCV004846715	uncertain significance	BRCA2-related cancer predisposition	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 2059 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 reported for this variant. This variant has been reported in one individual each affected with breast and ovarian cancer (PMID: 24504028, 28503720). This variant has been identified in 1/250662 chromosomes 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.