ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.997A>G (p.Thr333Ala) (rs786201634)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV001003379 SCV001161513 benign Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000013
Ambry Genetics RCV000164011 SCV000214616 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-17 criteria provided, single submitter clinical testing The p.T333A variant (also known as c.997A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 997. The threonine at codon 333 is replaced by alanine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000701903 SCV000830726 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-03 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 333 of the BRCA1 protein (p.Thr333Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 184709). Based on a multifactorial likelihood algorithm using genetic and statistical data, this variant has been determined to have a low probability of being pathogenic (PMID: 31131967). 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.
Color Health, Inc RCV000164011 SCV000909391 likely benign Hereditary cancer-predisposing syndrome 2017-06-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985454 SCV001133661 uncertain significance not provided 2018-10-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001003379 SCV001280983 uncertain significance Breast-ovarian cancer, familial 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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