Submissions for variant NM_000059.4(BRCA2):c.4288A>G (p.Thr1430Ala)

dbSNP: rs1555283691

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588421	SCV000694763	uncertain significance	not provided	2016-08-29	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.4288A>G (p.Thr1430Ala) variant involves the alteration of a conserved nucleotide located in the third BRCA2 repeat domain. 2/3 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 119436 control chromosomes. The variant has not been reported in affected individuals in the literature or databases, however functional studies suggest the variant to disrupt the interaction of BRCA2 and RAD51 (Davies_2001, Galkin_2005), which may alter HDR activity . Because of the absence of clinical information, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Ambry Genetics	RCV001022215	SCV001183923	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-20	criteria provided, single submitter	clinical testing	The p.T1430A variant (also known as c.4288A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4288. The threonine at codon 1430 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly 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	RCV002530889	SCV003313072	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-02-18	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1430 of the BRCA2 protein (p.Thr1430Ala). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. 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. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 11239456, 15937124). 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. ClinVar contains an entry for this variant (Variation ID: 495463).
University of Washington Department of Laboratory Medicine, University of Washington	RCV001022215	SCV003850385	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).