Submissions for variant NM_000059.4(BRCA2):c.9838C>T (p.Pro3280Ser)

gnomAD frequency: 0.00002  dbSNP: rs55835607

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045903	SCV000073916	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000487013	SCV000566872	uncertain significance	not provided	2018-12-21	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.9838C>T at the cDNA level, p.Pro3280Ser (P3280S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). Using alternate nomenclature, this variant would be defined as BRCA2 10066C>T. This variant showed complementation and homology directed repair capacity similar to wild type and did not significantly impact sensitivity to DNA damaging agents in in vitro functional studies (Mesman 2018). BRCA2 Pro3280Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Pro3280Ser is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Pro3280Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000509955	SCV000607793	likely benign	Hereditary cancer-predisposing syndrome	2020-02-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000509955	SCV000684093	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 3280 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). Functional studies have shown that this variant does not impact homology-directed DNA repair, cisplatin sensitivity, or complementation compared to wild-type BRCA2 (PMID: 29988080). This variant has been reported in two individuals affected with breast cancer (PMID: 31451522, 34178674). This variant has been identified in 4/251294 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	RCV001193233	SCV001361958	likely benign	not specified	2022-10-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9838C>T (p.Pro3280Ser) results in a non-conservative amino acid change in 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 1.6e-05 in 251294 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9838C>T has been reported in the literature in individuals affected with Breast Cancer without evidence of causality (Ebrahimi_2019, Fanale_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.5145delC, BIC; BRCA2 c.755_758delACAG, UMD), providing supporting evidence for a benign role. A mouse embryonic stem cell (mESC)-based functional assay showed the variant to have proper complementation to loss of endogenous Brca2 and 125% HDR capacity compared to wild-type (Mesman_2018). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two laboratories classified it as uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Sharing Clinical Reports Project (SCRP)	RCV000077476	SCV000109274	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2010-09-09	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077476	SCV000145718	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing