Submissions for variant NM_007294.4(BRCA1):c.4126A>G (p.Thr1376Ala)

gnomAD frequency: 0.00001  dbSNP: rs576828558

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001021919	SCV001183595	uncertain significance	Hereditary cancer-predisposing syndrome	2018-04-12	criteria provided, single submitter	clinical testing	The p.T1376A variant (also known as c.4126A>G), located in coding exon 10 of the BRCA1 gene, results from an A to G substitution at nucleotide position 4126. The threonine at codon 1376 is replaced by alanine, an amino acid with similar properties. This amino acid position is poorly 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.
Invitae	RCV001862197	SCV002126562	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-15	criteria provided, single submitter	clinical testing	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. 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 BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 824612). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1376 of the BRCA1 protein (p.Thr1376Ala).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492209	SCV004240264	uncertain significance	Breast and/or ovarian cancer	2023-03-01	criteria provided, single submitter	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250716	SCV002520861	uncertain significance	Familial cancer of breast		no assertion criteria provided	curation