Submissions for variant NM_000059.4(BRCA2):c.5284T>G (p.Tyr1762Asp)

gnomAD frequency: 0.00001  dbSNP: rs1192019733

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000575439	SCV000668572	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-24	criteria provided, single submitter	clinical testing	The p.Y1762D variant (also known as c.5284T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 5284. The tyrosine at codon 1762 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This amino acid position is not well 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	RCV000706689	SCV000835756	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 1762 of the BRCA2 protein (p.Tyr1762Asp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer and/or Lynch syndrome (PMID: 25980754, 35264596). ClinVar contains an entry for this variant (Variation ID: 482984). 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.
Color Diagnostics, LLC DBA Color Health	RCV000575439	SCV000913140	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000989039	SCV001139111	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284427	SCV001470220	uncertain significance	not provided	2024-09-12	criteria provided, single submitter	clinical testing	The BRCA2 c.5284T>G (p.Tyr1762Asp) variant has been reported in the published literature in individuals with breast cancer (PMID: 35264596 (2022)) and a Lynch syndrome associated cancer and/or polyps (PMID: 25980754 (2015)). This variant has also been reported to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000008 (2/250334 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV001284427	SCV001759849	uncertain significance	not provided	2024-12-05	criteria provided, single submitter	clinical testing	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 5512T>G; This variant is associated with the following publications: (PMID: 25980754, 35264596, 29884841, 32377563)
Baylor Genetics	RCV000989039	SCV002030236	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2021-02-09	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV000575439	SCV002536122	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000575439	SCV003847143	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).