Submissions for variant NM_007294.4(BRCA1):c.1030G>A (p.Ala344Thr)

gnomAD frequency: 0.00001  dbSNP: rs79727659

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000581734	SCV000688312	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000111530	SCV000785549	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-11-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985363	SCV001133474	uncertain significance	not provided	2019-02-28	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/251244 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a large-scale breast cancer association study, the variant was observed in an individual with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). This variant co-occurred with a pathogenic variant in the BRCA1 gene in individuals from our internal patient population, suggesting it may not be the primary cause of disease. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001327254	SCV001518320	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 344 of the BRCA1 protein (p.Ala344Thr). This variant is present in population databases (rs79727659, gnomAD 0.002%). This missense change has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 16267036). ClinVar contains an entry for this variant (Variation ID: 54104). 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 BRCA1 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV000581734	SCV002696339	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-17	criteria provided, single submitter	clinical testing	The p.A344T variant (also known as c.1030G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1030. The alanine at codon 344 is replaced by threonine, 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000581734	SCV003846219	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).
GeneDx	RCV000985363	SCV005385740	uncertain significance	not provided	2024-04-22	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer and in unaffected controls (PMID: 33471991); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 1149G>A; This variant is associated with the following publications: (PMID: 20215511, 11521194, 10426999, 9582019, 9926942, 15343273, 32377563, 33471991, 29884841, 31131967, 16267036)
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111530	SCV000143985	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000111530	SCV004244139	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing