ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4480G>A (p.Glu1494Lys)

gnomAD frequency: 0.00001  dbSNP: rs80357148
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048568 SCV000076581 likely benign Hereditary breast ovarian cancer syndrome 2024-01-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000566435 SCV000665802 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-10 criteria provided, single submitter clinical testing The p.E1494K variant (also known as c.4480G>A), located in coding exon 12 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4480. The glutamic acid at codon 1494 is replaced by lysine, an amino acid with similar properties. This alteration had near wildtype transcription activation activity, however, this alteration does not lie in the BRCA1 transactivation or coiled-coil domains which casts doubt on the clinical interpretation of these data (Woods NT et al. NPJ Genom Med, 2016 Mar;1:). This amino acid position is poorly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588631 SCV000699151 uncertain significance not provided 2017-01-06 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4480G>A (p.Glu1494Lys) variant involves the alteration of a non-conserved nucleotide and is outside of some commonly known BRCA1 domains (RING, S-R and BRCT) (InterPro). 4/4 in silico tools predict a benign outcome for this variant. This variant was found in 1/121368 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). In literature, this variant has been reported in one HBOC patient without strong evidence for pathogenicity (Judkins _2005/BIC). One clinical diagnostic laboratory and a reputable database have classified this variant as uncertain significance. Taken together, this variant is classified as Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588631 SCV000887696 uncertain significance not provided 2018-06-08 criteria provided, single submitter clinical testing
GeneDx RCV000588631 SCV001818032 uncertain significance not provided 2022-12-12 criteria provided, single submitter clinical testing Published functional studies demonstrate approximately 80% transcription activity when compared to wild-type (Woods et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Observed in at least one individual referred for BRCA1/2 genetic testing (Judkins et al., 2005); Also known as 4599G>A; This variant is associated with the following publications: (PMID: 21520333, 10923033, 29884841, 15343273, 22737296, 16267036, 28781887, 32377563)
Color Diagnostics, LLC DBA Color Health RCV000566435 SCV004360178 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-21 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 1494 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has reported that this variant does not impact BRCA1 function in a transcription activation assay (PMID: 28781887). This variant has not been reported in individuals affected with BRCA1-related disorders in the literature. This variant has been identified in 2/282604 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112337 SCV000145092 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2004-11-25 no assertion criteria provided clinical testing

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