Submissions for variant NM_000059.4(BRCA2):c.8084C>T (p.Ser2695Leu)

dbSNP: rs80359048

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001703948	SCV000564797	likely benign	not provided	2019-03-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29387975, 24323938, 19043619, 22678057)
Ambry Genetics	RCV000509622	SCV000608046	likely benign	Hereditary cancer-predisposing syndrome	2020-02-25	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.
Color Diagnostics, LLC DBA Color Health	RCV000509622	SCV000906948	likely benign	Hereditary cancer-predisposing syndrome	2022-11-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001371246	SCV001567804	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2695 of the BRCA2 protein (p.Ser2695Leu). This variant is present in population databases (rs80359048, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 52500). 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: 22678057, 24323938). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307383	SCV002600621	likely benign	not specified	2022-10-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8084C>T (p.Ser2695Leu) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251296 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8084C>T has been reported in the literature in individuals affected with Breast Cancer (e.g. Biswas_2012, Caputo_2021, Dorling_2021), but the variant was found to poorly segregate with disease within families (Biswas_2012), giving a likelihood ratio that suggested neutrality and an IARC score of 1-benign (Caputo_2021). Co-occurrences with pathogenic variants have been reported (e.g. BRCA1 c.140G>A [p.Cys47Tyr]; BRCA2 c.9294C>A [p.Tyr3098Ter]; UMD database), providing supporting evidence for a benign role. Several publications have provided experimental evidence evaluating the impact of the variant on protein function and demonstrated there was no damaging effect: the variant was capable of complementing Brca2 knockout ES cells (Biswas_2012), was insensitive to DNA damaging agents (Biswas_2012), and had functional HDR activity (Biswas_2012, Richardson_2021). Four ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV001703948	SCV002822078	likely benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	BRCA2: PM2, BP4, BS3:Moderate
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002307383	SCV004243068	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113869	SCV000147268	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-06-20	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000113869	SCV000863746	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing