ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9907A>T (p.Ser3303Cys)

dbSNP: rs276174930
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167325 SCV000218175 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-21 criteria provided, single submitter clinical testing The p.S3303C variant (also known as c.9907A>T), located in coding exon 26 of the BRCA2 gene, results from an A to T substitution at nucleotide position 9907. The serine at codon 3303 is replaced by cysteine, an amino acid with dissimilar properties. This alteration was previously detected in one Malaysian high-risk breast and/or ovarian cancer family (Thirthagiri E, Breast Cancer Res. 2008 ; 10(4):R59). This variant was also reported in 1/60,466 breast cancer cases and in 0/53,461 controls (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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000454487 SCV000538496 uncertain significance not specified 2016-06-16 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 paper; ClinVar: 2 VUS
Color Diagnostics, LLC DBA Color Health RCV000167325 SCV001350585 uncertain significance Hereditary cancer-predisposing syndrome 2023-10-05 criteria provided, single submitter clinical testing This missense variant replaces serine with cysteine at codon 3303 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). A functional study in mouse embryonic stem cells has shown this variant does not impact sensitivity to DNA damaging agents (PMID: 33314489). This variant has been reported in at least one individual affected with breast cancer (PMID: 18627636, 33471991; Leiden Open Variation Database DB-ID BRCA2_003783). 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.
Invitae RCV001302458 SCV001491668 uncertain significance Hereditary breast ovarian cancer syndrome 2023-06-14 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 33314489). 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. ClinVar contains an entry for this variant (Variation ID: 52914). This missense change has been observed in individual(s) with breast cancer (PMID: 18627636, 33314489). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 3303 of the BRCA2 protein (p.Ser3303Cys).
Breast Cancer Information Core (BIC) (BRCA2) RCV000112821 SCV000145728 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2010-09-18 no assertion criteria provided clinical testing

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