Submissions for variant NM_000059.4(BRCA2):c.2104A>G (p.Ile702Val)

dbSNP: rs774968533

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000539846	SCV000635204	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-02-26	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 702 of the BRCA2 protein (p.Ile702Val). This variant is present in population databases (rs774968533, 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: 462257). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755869	SCV000883499	uncertain significance	not provided	2018-01-25	criteria provided, single submitter	clinical testing	The BRCA2 c.2104A>G; p.Ile702Val variant (rs774968533) is not reported in the literature or gene specific databases but is reported as uncertain one time in ClinVar (Variation ID: 462257). This variant is seen in the general population at a low overall frequency of 0.0004% (1/245908 alleles) in the Genome Aggregation Database. The isoleucine at codon 702 is weakly conserved and computational algorithms (SIFT, MutationTaster, Align GVGD) predict this variant to be tolerated. However, given the lack of clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty.
University of Washington Department of Laboratory Medicine, University of Washington	RCV003157642	SCV003846501	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000755869	SCV004219532	uncertain significance	not provided	2022-10-13	criteria provided, single submitter	clinical testing	The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000004 (1/250722 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Department of Medical and Surgical Sciences, University of Bologna	RCV003483660	SCV004228384	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	PM2(Supporting)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)