Submissions for variant NM_000059.4(BRCA2):c.1993A>G (p.Thr665Ala)

gnomAD frequency: 0.00002  dbSNP: rs144192844

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130109	SCV000184939	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-20	criteria provided, single submitter	clinical testing	The p.T665A variant (also known as c.1993A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 1993. The threonine at codon 665 is replaced by alanine, an amino acid with similar 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.
GeneDx	RCV000586597	SCV000210279	uncertain significance	not provided	2019-11-22	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as 2221A>G
Eurofins Ntd Llc (ga)	RCV000586597	SCV000225157	uncertain significance	not provided	2015-03-17	criteria provided, single submitter	clinical testing
Counsyl	RCV000239179	SCV000488922	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-07-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466395	SCV000549527	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 665 of the BRCA2 protein (p.Thr665Ala). This variant is present in population databases (rs144192844, gnomAD 0.01%). 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: 141539). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420707	SCV000694587	uncertain significance	not specified	2023-10-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1993A>G (p.Thr665Ala) 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 allele was found at a frequency of 8.1e-06 in 247100 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, c.1993A>G has not been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. It has however been reported as a VUS in at-least one individual with hypodiplpoid ALL (Zhang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=7; Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586597	SCV000888996	uncertain significance	not provided	2024-08-07	criteria provided, single submitter	clinical testing	The BRCA2 c.1993A>G (p.Thr665Ala) variant has been reported in the published literature in in an individual with leukemia in a pediatric cancer study (PMID: 26580448 (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, 0.00012 (3/24846 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.
Color Diagnostics, LLC DBA Color Health	RCV000130109	SCV000906499	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-30	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130109	SCV003846431	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).
All of Us Research Program, National Institutes of Health	RCV004804147	SCV005424309	uncertain significance	BRCA2-related cancer predisposition	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 665 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypodiploid ALL (PMID: 26580448). This variant has been identified in 2/247100 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.