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

gnomAD frequency: 0.00001  dbSNP: rs1192019733

Total submissions: 10

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, 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.
Invitae	RCV000706689	SCV000835756	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-09	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). 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.
Mendelics	RCV000706689	SCV000838812	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
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	2020-10-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001284427	SCV001759849	uncertain significance	not provided	2019-07-29	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25980754)
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).