ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4884G>T (p.Met1628Ile)

dbSNP: rs80357158
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000112416 SCV000489344 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2016-09-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000573448 SCV000665921 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-19 criteria provided, single submitter clinical testing The p.M1628I variant (also known as c.4884G>T), located in coding exon 14 of the BRCA1 gene, results from a G to T substitution at nucleotide position 4884. The methionine at codon 1628 is replaced by isoleucine, an amino acid with highly similar properties. Two separate transcription activation assays found that this variant had >80% activity relative to wildtype and was, thus, considered neutral (Woods NT et al. NPJ Genom Med, 2016 Mar;1:16001; Fernandes VC et al. J Biol Chem, 2019 Apr;294:5980-5992). 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.
Invitae RCV001300632 SCV001489779 uncertain significance Hereditary breast ovarian cancer syndrome 2022-04-29 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1628 of the BRCA1 protein (p.Met1628Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 10923033; Invitae). ClinVar contains an entry for this variant (Variation ID: 55307). 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. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 28781887). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001582549 SCV001821271 uncertain significance not specified 2021-08-15 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4884G>T (p.Met1628Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251392 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4884G>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported in the literature. At-least one co-occurrence with another pathogenic variant has been reported in the BIC database (BRCA2 c.9253_9254insA, HGVS c.9253dupA, p.Thr3085?fs, HGVS p.Thr3085Asnfs), providing supporting evidence for a benign role. At least two publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in a transcriptional activation assay system resulting in a categorization as "non pathogenic", fClass 1 variant (example, Woods_2016, Fernandes_2019). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112416 SCV000145202 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2004-02-20 no assertion criteria provided clinical testing

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