ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1135A>G (p.Ile379Val) (rs864622723)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204469 SCV000262150 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-04-15 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 379 of the BRCA1 protein (p.Ile379Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 221036). 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 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, 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.
Ambry Genetics RCV000568268 SCV000668479 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-06 criteria provided, single submitter clinical testing Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000779855 SCV000916719 uncertain significance not specified 2018-10-04 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1135A>G (p.Ile379Val) results in a conservative amino acid change located in the serine-rich domain (IPR025994) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 276870 control chromosomes (GnomAD). 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.1135A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have 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 uncertain significance.

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