Submissions for variant NM_000059.4(BRCA2):c.7464A>C (p.Arg2488Ser)

dbSNP: rs80358969

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164219	SCV000214840	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	RCV000164219	SCV000683874	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-31	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 2488 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant does not impact homology-directed DNA repair (PMID: 29394989, 35736817) and does not impact cell viability or drug sensitivity in Brca2-deficient mouse embryonic stem cells (PMID: 33293522). To our knowledge, this variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 1/251420 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759655	SCV000889126	uncertain significance	not provided	2019-02-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001110755	SCV001268230	uncertain significance	Fanconi anemia complementation group D1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000113764	SCV001268231	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001305633	SCV001494975	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 2488 of the BRCA2 protein (p.Arg2488Ser). This variant is present in population databases (rs80358969, 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: 52337). 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: 29394989, 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.
GeneDx	RCV000759655	SCV001776388	uncertain significance	not provided	2019-10-09	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: homology-directed repair activity consistent with neutrality (Guidugli 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as: BRCA2 7692A>C; This variant is associated with the following publications: (PMID: 29884841, 31422574, 19043619, 29394989)
All of Us Research Program, National Institutes of Health	RCV004803897	SCV004844408	uncertain significance	BRCA2-related cancer predisposition	2024-03-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004566836	SCV005059076	uncertain significance	Familial cancer of breast	2024-02-06	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113764	SCV000147096	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113764	SCV000297551	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-09-14	no assertion criteria provided	clinical testing