Submissions for variant NM_000059.4(BRCA2):c.3797A>G (p.His1266Arg)

dbSNP: rs1555283399

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001207278	SCV001378622	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-04-06	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 1266 of the BRCA2 protein (p.His1266Arg). 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: 938122). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298904	SCV002599031	uncertain significance	not specified	2022-09-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002365936	SCV002625832	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-01	criteria provided, single submitter	clinical testing	The p.H1266R variant (also known as c.3797A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 3797. The histidine at codon 1266 is replaced by arginine, an amino acid with highly similar properties. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002365936	SCV003846881	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).
Color Diagnostics, LLC DBA Color Health	RCV002365936	SCV004362023	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 1266 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has not been identified 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	RCV004010661	SCV004834218	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 1266 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has not been identified 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.