Submissions for variant NM_000059.4(BRCA2):c.2287C>G (p.His763Asp)

gnomAD frequency: 0.00001  dbSNP: rs863224585

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200091	SCV000254173	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 763 of the BRCA2 protein (p.His763Asp). This variant is present in population databases (no rsID available, 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: 216240). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Department of Pathology and Molecular Medicine, Queen's University	RCV000496468	SCV000588082	uncertain significance	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563152	SCV000668567	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	The p.H763D variant (also known as c.2287C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 2287. The histidine at codon 763 is replaced by aspartic acid, an amino acid with 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.
Color Diagnostics, LLC DBA Color Health	RCV000563152	SCV000906038	likely benign	Hereditary cancer-predisposing syndrome	2017-09-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985474	SCV001133707	uncertain significance	not provided	2019-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000985474	SCV001820497	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 2515C>G; This variant is associated with the following publications: (PMID: 32377563, 29884841, 31853058, 28726806)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496468	SCV002041861	uncertain significance	not specified	2021-11-17	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000563152	SCV003848199	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).
All of Us Research Program, National Institutes of Health	RCV003996985	SCV004847036	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-07	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358320	SCV001554020	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.His763Asp variant was not identified in the literature nor was it identified in the LOVD 3.0 or UMD LSDB databases. The variant was identified in dSNP (rs863224585) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and COGR). The variant was identified in control databases in 1 of 30954 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the Other population in 1 of 982 chromosomes (freq: 0.001), while the variant was not observed in the European, African, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.His763 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.