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

dbSNP: rs56055578

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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	2022-03-25	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	2023-06-29	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported as part of a haplotype seen in patients with breast cancer in the published literature (PMID: 16267036 (2005)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Invitae	RCV001367617	SCV001563973	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-10-25	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 55041). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 10923033). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 130 of the BRCA1 protein (p.Tyr130Phe).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112438	SCV000145228	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2006-07-19	no assertion criteria provided	clinical testing