Submissions for variant NM_000059.4(BRCA2):c.9383G>A (p.Arg3128Gln)

gnomAD frequency: 0.00002  dbSNP: rs397507427

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130023	SCV000184849	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705810	SCV000834825	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 3128 of the BRCA2 protein (p.Arg3128Gln). This variant is present in population databases (rs397507427, gnomAD 0.03%). 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: 38236). 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: 37731132). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985626	SCV001133979	uncertain significance	not provided	2018-10-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130023	SCV001357093	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 3128 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). To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 2/53461 unaffected controls (PMID: 33471991; p-value=1; Leiden Open Variation Database DB-ID BRCA2_003182). This variant has been identified in 5/251358 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.
All of Us Research Program, National Institutes of Health	RCV004803093	SCV004846165	uncertain significance	BRCA2-related cancer predisposition	2024-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 3128 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). To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 2/53461 unaffected controls (PMID: 33471991; p-value=1; Leiden Open Variation Database DB-ID BRCA2_003182). This variant has been identified in 5/251358 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.
Sharing Clinical Reports Project (SCRP)	RCV000031819	SCV000054427	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500827	SCV000592282	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Arg3128Gln variant has not been reported in the literature nor previously identified by our laboratory. This residue is not conserved in mammals and the variant amino acid Gln (Glutamine) is present in other species (mouse and chicken) decreasing the likelihood that this variant has clinical significance. Computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.