ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.389A>T (p.Tyr130Phe) (rs56055578)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000152869 SCV000202275 uncertain significance not provided 2014-03-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000510086 SCV000607831 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-30 criteria provided, single submitter clinical testing The p.Y130F variant (also known as c.389A>T), located in coding exon 5 of the BRCA1 gene, results from an A to T substitution at nucleotide position 389. The tyrosine at codon 130 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, phenylalanine is the reference amino acid in several 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781013 SCV000918765 likely benign not specified 2018-07-24 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.389A>T (p.Tyr130Phe) results in a conservative amino acid change located in the RING-finger-containing E3 ubiquitin ligase domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246248 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.389A>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported in at least 3 individuals, including one internal LCA sample (BRCA1 c.391A>T, p.R131*), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as Likely Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000152869 SCV001469997 uncertain significance not provided 2019-09-23 criteria provided, single submitter clinical testing
Invitae RCV001367617 SCV001563973 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-04-08 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with phenylalanine at codon 130 of the BRCA1 protein (p.Tyr130Phe). The tyrosine residue is moderately conserved and there is a small physicochemical difference between tyrosine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 55041). 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 C0. The phenylalanine amino acid residue is 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 and their clinical significance is uncertain. 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112438 SCV000145228 uncertain significance Breast-ovarian cancer, familial 1 2006-07-19 no assertion criteria provided clinical testing

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