Submissions for variant NM_000059.4(BRCA2):c.4464C>A (p.His1488Gln)

dbSNP: rs786203743

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167179	SCV000218013	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-29	criteria provided, single submitter	clinical testing	The p.H1488Q variant (also known as c.4464C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 4464. The histidine at codon 1488 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is poorly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814203	SCV000954604	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-16	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1488 of the BRCA2 protein (p.His1488Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 187450). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284425	SCV001470217	uncertain significance	not provided	2024-08-14	criteria provided, single submitter	clinical testing	The BRCA2 c.4464C>A (p.His1488Gln) variant has been reported in the published literature in individuals with cardiac angiosarcoma (PMID: 31510873 (2019)) and individuals with personal or family history of an unspecified cancer (PMID: 31853058 (2020)). This variant has been described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000167179	SCV003850529	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	RCV001284425	SCV003927560	uncertain significance	not provided	2023-05-26	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; Observed in an individual with unspecified personal and/or family history of cancer undergoing multi-gene panel testing (Li et al., 2020); This variant is associated with the following publications: (PMID: 31853058, 32377563, 29884841, 31911673)
PreventionGenetics, part of Exact Sciences	RCV004528919	SCV004109545	uncertain significance	BRCA2-related disorder	2023-05-25	criteria provided, single submitter	clinical testing	The BRCA2 c.4464C>A variant is predicted to result in the amino acid substitution p.His1488Gln. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/187450/). This variant occurs within a region of the BRCA2 gene that is predicted to be tolerant to variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398856	SCV004122584	uncertain significance	not specified	2023-10-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4464C>A (p.His1488Gln) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250492 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4464C>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=4) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.