Submissions for variant NM_000059.4(BRCA2):c.3668A>G (p.His1223Arg)

dbSNP: rs398122768

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000800645	SCV000940374	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-13	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 1223 of the BRCA2 protein (p.His1223Arg). 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: 91804). 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.
GeneDx	RCV001562627	SCV001785422	uncertain significance	not provided	2023-01-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 3896A>G; Observed in at least one individual with breast and/or ovarian cancer (Apessos et al., 2018; This variant is associated with the following publications: (PMID: 18288416, 24312913, 12872263, 31911673, 32377563, 9002670, 22193408, 29884841, 29310832)
Ambry Genetics	RCV002453393	SCV002613513	likely benign	Hereditary cancer-predisposing syndrome	2021-08-13	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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002453393	SCV003846780	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).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321501	SCV004027420	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077712	SCV000109515	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-01-11	no assertion criteria provided	clinical testing