Submissions for variant NM_000059.4(BRCA2):c.8115C>G (p.Ser2705Arg)

dbSNP: rs587781889

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130221	SCV000185060	likely benign	Hereditary cancer-predisposing syndrome	2019-12-06	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.
Counsyl	RCV000411253	SCV000487899	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130221	SCV000683941	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-22	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 2705 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 has reported that this variant does not impact BRCA2 function in a homology-directed repair assay (PMID: 29884841). This variant has been detected in a hereditary breast cancer family, however, it does not co-segregate with breast cancer in the carrier family (PMID: 20960228). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000796695	SCV000936218	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 2705 of the BRCA2 protein (p.Ser2705Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with high risk of breast and/or ovarian cancer (PMID: 20960228). This variant is also known as c.8343C>G. ClinVar contains an entry for this variant (Variation ID: 141626). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 29884841). 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237738	SCV002010317	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000411253	SCV004845601	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 2705 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 has reported that this variant does not impact BRCA2 function in a homology-directed repair assay (PMID: 29884841). This variant has been detected in a hereditary breast cancer family, however, it does not co-segregate with breast cancer in the carrier family (PMID: 20960228). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.