Submissions for variant NM_000059.4(BRCA2):c.931T>C (p.Cys311Arg)

dbSNP: rs61754140

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001337541	SCV001531147	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-07-30	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 311 of the BRCA2 protein (p.Cys311Arg). This variant is not present in population databases (gnomAD no frequency). 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: 1034772). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV003158755	SCV003848144	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357899	SCV001553499	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Cys311Arg variant was not identified in the literature nor was it identified in the dbSBP, ClinVar, Genesight-COGR, Cosmic, MutDB, UMD-LSDB, BIC Database, ARUP Laboratories, Zhejiang University Database databases. The variant was identified in the LOVD 3.0 database (1x in a breast cancer patient classified as effect unknown by the Netherlands Cancer Institute). The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (February 27, 2017) control databases, however a different nucleotide substitution at this position (c.931T>G, p.Cys311Gly) was found under the same dbSNP number (rs61754140) in 2 South Asian individuals in the Genome Aggregation Database (frequency 0.000009). The p.Cys311Arg residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located within the DNA recombination and repair protein, BRCA2 functional domains increasing the likelihood that it may have clinical significance. 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 uncertain significance.