Submissions for variant NM_000059.4(BRCA2):c.6062A>G (p.His2021Arg)

dbSNP: rs780621780

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165232	SCV000215946	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-29	criteria provided, single submitter	clinical testing	The p.H2021R variant (also known as c.6062A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 6062. The histidine at codon 2021 is replaced by arginine, an amino acid with highly similar properties. This variant was identified in an Italian breast/ovarian cancer cohort (Zuntini R et al. Front Genet, 2018 Sep;9:378). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588995	SCV000694932	uncertain significance	not provided	2017-01-23	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.6062A>G (p.His2021Arg) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant is absent in 120670 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. UMD lists the variant in one individual with a co-occurrence with a pathogenic BRCA2 c.4889C>G (p.Ser1630X, classified as pathogenic by LCA) variant suggesting neutrality. One clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, the variant was classified as VUS-possibly benign.
Color Diagnostics, LLC DBA Color Health	RCV000165232	SCV000906126	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001364172	SCV001560307	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-01	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 2021 of the BRCA2 protein (p.His2021Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 30254663). ClinVar contains an entry for this variant (Variation ID: 185748). 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	RCV000165232	SCV003850891	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	RCV000588995	SCV005624482	uncertain significance	not provided	2024-06-11	criteria provided, single submitter	clinical testing	The BRCA2 c.6062A>G (p.His2021Arg) variant has been reported in the published literature to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). In addition, this variant has been identified in an individual undergoing multigene panel testing (PMID: 31853058 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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	RCV003483536	SCV004228424	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)