ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.926A>C (p.Lys309Thr)

dbSNP: rs80356877
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV002253207 SCV002525240 uncertain significance not provided 2022-05-20 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 1045A>C; This variant is associated with the following publications: (PMID: 20215511, 15343273, 9926942, 9582019, 11521194, 23704879, 25011685)
Sema4, Sema4 RCV002257396 SCV002537929 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-09 criteria provided, single submitter curation
Ambry Genetics RCV002257396 SCV002686847 uncertain significance Hereditary cancer-predisposing syndrome 2022-05-12 criteria provided, single submitter clinical testing The p.K309T variant (also known as c.926A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 926. The lysine at codon 309 is replaced by threonine, an amino acid with similar properties. This variant was predicted to affect substrate binding by the NetworKIN in silico tool (Tram E et al. PLoS One, 2013 May;8:e62468). 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV002257396 SCV003846286 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).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV002253207 SCV004219482 uncertain significance not provided 2022-11-01 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.000004 (1/251376 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been predicted to negatively impact protein function (PMID: 23704879 (2013)). However, the variant has also been predicted to have no impact on protein function (PMID: 33087888 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Invitae RCV003529976 SCV004296849 uncertain significance Hereditary breast ovarian cancer syndrome 2023-12-10 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 309 of the BRCA1 protein (p.Lys309Thr). This variant is present in population databases (rs80356877, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 55756). 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 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111512 SCV000143954 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2004-11-25 no assertion criteria provided clinical testing

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