Submissions for variant NM_000059.4(BRCA2):c.6709G>C (p.Asp2237His)

gnomAD frequency: 0.00001  dbSNP: rs1174104045

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000581060	SCV000683804	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758931	SCV000887885	uncertain significance	not provided	2022-07-30	criteria provided, single submitter	clinical testing	The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000058 (2/34560 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Ambry Genetics	RCV000581060	SCV001187766	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-27	criteria provided, single submitter	clinical testing	The p.D2237H variant (also known as c.6709G>C), located in coding exon 10 of the BRCA2 gene, results from a G to C substitution at nucleotide position 6709. The aspartic acid at codon 2237 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853868	SCV002205454	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-15	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 2237 of the BRCA2 protein (p.Asp2237His). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 489775). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000581060	SCV003847387	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).
Myriad Genetics, Inc.	RCV003316753	SCV004020268	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-03-10	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].