ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1573G>A (p.Val525Ile) (rs80357273)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214482 SCV000273956 likely benign Hereditary cancer-predisposing syndrome 2015-09-27 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077491 SCV000144135 uncertain significance Breast-ovarian cancer, familial 1 2006-07-19 no assertion criteria provided clinical testing
Color RCV000214482 SCV000903404 likely benign Hereditary cancer-predisposing syndrome 2016-01-14 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000417626 SCV000591343 likely benign not specified 2014-05-14 criteria provided, single submitter clinical testing
GeneDx RCV000417626 SCV000512287 likely benign not specified 2018-03-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000417626 SCV000916761 uncertain significance not specified 2018-06-18 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1573G>A (p.Val525Ile) 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 allele was found at a frequency of 1.8e-05 in 276034 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1573G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and pancreatic cancer. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, including VUS (1x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as VUS.
Invitae RCV000047530 SCV000075543 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 525 of the BRCA1 protein (p.Val525Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs80357273, ExAC 0.01%). This variant has been reported in individuals affected with pancreatic, breast and/or ovarian cancer (PMID: 23961350, 28767289). ClinVar contains an entry for this variant (Variation ID: 54298). 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 isoleucine 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. 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.
Sharing Clinical Reports Project (SCRP) RCV000077491 SCV000109289 likely benign Breast-ovarian cancer, familial 1 2009-06-18 no assertion criteria provided clinical testing

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