ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3562A>G (p.Ile1188Val) (rs202230438)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132042 SCV000187102 likely benign Hereditary cancer-predisposing syndrome 2018-12-05 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
GeneDx RCV000034438 SCV000210529 uncertain significance not provided 2018-06-14 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3562A>G at the cDNA level, p.Ile1188Val (I1188V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). Using alternate nomenclature, this variant would be defined as 3790A>G. This variant has been observed in at least three individuals with breast cancer, as well as in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Kr?lewska 2004, Johnston 2012, Goidescu 2018). BRCA2 Ile1188Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Ile1188Val is located in the RAD51 binding domain (Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ile1188Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000465606 SCV000549504 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-08-08 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1188 of the BRCA2 protein (p.Ile1188Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs202230438, ExAC 0.001%). This variant has been observed in several individuals affected with breast cancer (PMID: 29785153) and in an individual undergoing genetic testing for hereditary cancer predisposition (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 41547). 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, 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.
GeneKor MSA RCV000132042 SCV000821935 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132042 SCV000903241 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779929 SCV000916868 uncertain significance not specified 2021-01-27 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3562A>G (p.Ile1188Val) 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 4e-06 in 251048 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3562A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Johnston_2012, Krolewska_2004, Goidescu_2018, Tsaousis_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=4, likely benign n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034438 SCV000043206 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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