ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3409A>G (p.Met1137Val) (rs771479616)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000527157 SCV000635896 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 1137 of the BRCA1 protein (p.Met1137Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs771479616, ExAC 0.01%). This variant has been observed in an individual affected with breast or ovarian cancer (PMID: 28364669). ClinVar contains an entry for this variant (Variation ID: 462610). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine 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, this variant has uncertain impact on BRCA1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000568958 SCV000665803 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-03 criteria provided, single submitter clinical testing Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000587353 SCV000699030 uncertain significance not provided 2016-07-05 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3409A>G (p.Met1137Val) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). Met1137 is not located in any known functional domain of the Breast cancer type 1 susceptibility protein and is not highly conserved across species. This variant was found in 1/121210 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. One database classified the variant as a VUS. In the absence of clinical information and functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color RCV000568958 SCV000909305 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-05 criteria provided, single submitter clinical testing

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