Submissions for variant NM_000059.4(BRCA2):c.28A>G (p.Thr10Ala)

dbSNP: rs786203080

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166222	SCV000217001	likely benign	Hereditary cancer-predisposing syndrome	2023-06-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470603	SCV000549561	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-13	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 10 of the BRCA2 protein (p.Thr10Ala). This variant is not present in population databases (gnomAD no frequency). 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: 186603). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 31843900; Invitae). 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.
GeneDx	RCV000586386	SCV000572250	uncertain significance	not provided	2021-12-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with breast, ovarian, endometrial, or colorectal cancer (Casadei 2019); Also known as 256A>G; This variant is associated with the following publications: (PMID: 31843900)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001171391	SCV000694644	uncertain significance	not specified	2022-05-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.28A>G (p.Thr10Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251392 control chromosomes. 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.28A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least two co-occurrences with other pathogenic variant(s) have been reported in the UMD database (BRCA2 c.2701delC, p.Ala902LeufsX2; BRCA1 c.3839_3841delCTC, p.Ser1280X), providing supporting evidence for a benign role. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3; Likely Benign/Benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000166222	SCV000903898	likely benign	Hereditary cancer-predisposing syndrome	2016-06-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474874	SCV004211940	uncertain significance	Familial cancer of breast	2023-09-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995490	SCV004846356	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-04-10	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV001171391	SCV001251292	benign	not specified	2019-09-01	no assertion criteria provided	research