ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3724A>G (p.Thr1242Ala) (rs80357037)

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Total submissions: 8
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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) RCV000112166 SCV001161587 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 = 0.000025
Invitae RCV000048305 SCV000076318 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-15 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1242 of the BRCA1 protein (p.Thr1242Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs80357037, ExAC 0.01%). This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 28993434, 16267036). ClinVar contains an entry for this variant (Variation ID: 54982). Based on a multifactorial likelihood algorithm using genetic, in silico, 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.
Ambry Genetics RCV000130029 SCV000184855 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-05 criteria provided, single submitter clinical testing The p.T1242A variant (also known as c.3724A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 3724. The threonine at codon 1242 is replaced by alanine, an amino acid with similar properties. This alteration has been detected in 1/2575 unselected patients with breast cancer and 0/2809 healthy control individuals from a Malaysian cohort (Wen WX et al. J. Med. Genet. 2018 02;55:97-103). This amino acid position is not well 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.
GeneDx RCV000212175 SCV000210154 likely benign not provided 2019-12-02 criteria provided, single submitter clinical testing Not observed at a significant frequency 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; This variant is associated with the following publications: (PMID: 28993434, 16267036, 31131967)
Color Health, Inc RCV000130029 SCV000909585 likely benign Hereditary cancer-predisposing syndrome 2016-07-14 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212175 SCV001151329 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001662157 SCV001878330 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Breast Cancer Information Core (BIC) (BRCA1) RCV000112166 SCV000144852 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing

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