ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.758C>T (p.Ala253Val)

dbSNP: rs1555593177
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000580159 SCV000683353 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-25 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 253 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985445 SCV001133645 uncertain significance not provided 2019-11-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000580159 SCV001189005 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-09 criteria provided, single submitter clinical testing The p.A253V variant (also known as c.758C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 758. The alanine at codon 253 is replaced by valine, an amino acid with similar properties. This amino acid position is 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.
Invitae RCV001320781 SCV001511579 uncertain significance Hereditary breast ovarian cancer syndrome 2021-10-07 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 253 of the BRCA1 protein (p.Ala253Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). 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: 489737). 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. 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 RCV000985445 SCV001991741 uncertain significance not provided 2019-07-30 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
University of Washington Department of Laboratory Medicine, University of Washington RCV000580159 SCV003847964 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).

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