ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3724A>G (p.Thr1242Ala) (rs80357037)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048305 SCV000076318 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-22 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: 16267036). ClinVar contains an entry for this variant (Variation ID: 54982). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). The alanine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and an affected individual, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000130029 SCV000184855 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000212175 SCV000210154 uncertain significance not provided 2018-02-23 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3724A>G at the cDNA level, p.Thr1242Ala (T1242A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). Using alternate nomenclature, this variant would be defined as BRCA1 3843A>G. This variant has been observed in at least one individual undergoing clinical BRCA1 testing (Judkins 2005). BRCA1 Thr1242Ala was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Thr1242Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000130029 SCV000909585 likely benign Hereditary cancer-predisposing syndrome 2016-07-14 criteria provided, single submitter clinical testing
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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