Submissions for variant NM_000059.4(BRCA2):c.3515C>G (p.Ser1172Trp)

dbSNP: rs80358600

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044212	SCV000072225	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 1172 of the BRCA2 protein (p.Ser1172Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 25896959, 32772980, 35263119). ClinVar contains an entry for this variant (Variation ID: 51480). 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. 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	RCV000222703	SCV000275647	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-01	criteria provided, single submitter	clinical testing	The p.S1172W variant (also known as c.3515C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 3515. The serine at codon 1172 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration has been detected in multiple breast cancer cohorts (D'Argenio V et al. Clin. Chim. Acta, 2015 Jun;446:221-5; Wong-Brown MW et al. Breast Cancer Res Treat, 2015 Feb;150:71-80; Nguyen-Dumont T et al. Genet Res (Camb), 2020 08;102:e6; Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well 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.
Counsyl	RCV000077305	SCV000488043	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222703	SCV000537557	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-14	criteria provided, single submitter	clinical testing	This missense variant replaces serine with tryptophan at codon 1172 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 individuals affected with breast or ovarian cancer and in two individuals with a personal or family history of breast cancer (PMID: 25896959, 25682074, 32772980, 33471991; Leiden Open Variation Database DB-ID BRCA2_003877). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781071	SCV000918879	uncertain significance	not specified	2023-06-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3515C>G (p.Ser1172Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250824 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.3515C>G, has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Wong-Brown_2015, D'Argenio_2015, Delahunty_2022, Nguyen-Dumont_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25682074, 25896959, 35263119, 32772980). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified at VUS (n=5) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985504	SCV001133760	uncertain significance	not provided	2023-06-02	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 33471991 (2021), 32772980 (2020), and 25896959 (2015)). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000222703	SCV003846670	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	RCV000985504	SCV004039681	uncertain significance	not provided	2023-09-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3743C>G; This variant is associated with the following publications: (PMID: 25896959, 32772980, 24817641, 29884841, 32377563, 31131967, 25682074, 33471991, 35263119, 31853058)
All of Us Research Program, National Institutes of Health	RCV000077305	SCV004845177	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces serine with tryptophan at codon 1172 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 individuals affected with breast or ovarian cancer and in two individuals with a personal or family history of breast cancer (PMID: 25896959, 25682074, 32772980, 33471991; Leiden Open Variation Database DB-ID BRCA2_003877). 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000985504	SCV005199781	uncertain significance	not provided	2023-11-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077305	SCV000109102	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-07-26	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077305	SCV000146250	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV002513644	SCV003761498	not provided	BRCA2-related disorder		no assertion provided	phenotyping only	Variant classified as Uncertain significance and reported on 05-14-2019 by Lab or GTR ID 505849. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.