ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3800T>C (p.Leu1267Ser) (rs587782190)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130824 SCV000185720 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-13 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000589536 SCV000210156 uncertain significance not provided 2019-01-04 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3800T>C at the cDNA level, p.Leu1267Ser (L1267S) at the protein level, and results in the change of a Leucine to a Serine (TTA>TCA). Functional studies by Bouwman et al. (2013) suggest that BRCA1 Leu1267Ser may be a neutral variant based on insensitivity to cisplatin and ability to support growth similar to controls in BRCA1-deficient mouse embryonic stem cells. BRCA1 Leu1267Ser 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 Leu1267Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000460978 SCV000549344 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-05 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 1267 of the BRCA1 protein (p.Leu1267Ser). The leucine residue is moderately conserved and there is a large physicochemical difference between leucine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 142031). Experimental studies have shown that this missense change can restore cell growth and reduce sensitivity to PARP inhibitors in Brca1 mouse embryonic stem cells suggesting it does not affect protein function (PMID: 23867111). In summary, this variant is a rare missense change that is not expected to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000130824 SCV000688453 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589536 SCV000699074 uncertain significance not provided 2016-02-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589536 SCV000888900 uncertain significance not provided 2017-08-26 criteria provided, single submitter clinical testing

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