Submissions for variant NM_000059.4(BRCA2):c.2836G>C (p.Asp946His)

dbSNP: rs80358534

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222307	SCV000275581	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-25	criteria provided, single submitter	clinical testing	The p.D946H variant (also known as c.2836G>C), located in coding exon 10 of the BRCA2 gene, results from a G to C substitution at nucleotide position 2836. The aspartic acid at codon 946 is replaced by histidine, 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. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000222307	SCV000683505	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586610	SCV000694636	uncertain significance	not provided	2016-10-13	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.2836G>C (p.Asp946His) variant involves the alteration of a non-conserved nucleotide. This variant is not located in any known domain (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/120672 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been reported in two individuals by two clinical labs without strong evidence for pathogenicity. Multiple clinical diagnostic laboratories have classified this variant as uncertain significance. Because of the absence of sufficient clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637635	SCV000759102	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 946 of the BRCA2 protein (p.Asp946His). This variant is present in population databases (rs80358534, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 125996). 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	RCV000222307	SCV003850172	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).
GeneDx	RCV000586610	SCV005326575	uncertain significance	not provided	2024-02-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate cell viability and drug sensitivity comparable to wild type in mouse embryonic stem cells (PMID: 37922907); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3064G>C; This variant is associated with the following publications: (PMID: 29884841, 32377563, 29625052, 36451132, 23929434, 26689913, 31853058, 37922907)
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113100	SCV000146125	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing