ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3571A>G (p.Ile1191Val) (rs761405340)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166662 SCV000217467 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000166662 SCV000902870 likely benign Hereditary cancer-predisposing syndrome 2016-06-15 criteria provided, single submitter clinical testing
Counsyl RCV000662435 SCV000784894 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-01-27 criteria provided, single submitter clinical testing
GeneDx RCV000219026 SCV000279885 uncertain significance not provided 2018-10-22 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3571A>G at the cDNA level, p.Ile1191Val (I1191V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has been observed in at least two individuals diagnosed with breast cancer and two individuals diagnosed with pancreatic cancer, one of which also had a diagnosis of melanoma (Easton 2016, Jalkh 2017, Shindo 2017, Dudley 2018). BRIP1 Ile1191Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 BRIP1 Ile1191Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance
Integrated Genetics/Laboratory Corporation of America RCV000781167 SCV000919046 uncertain significance not specified 2017-11-20 criteria provided, single submitter clinical testing Variant summary: The BRIP1 variant, c.3571A>G (p.ile1191Val) involves a non-conserved nucleotide and 5/5 in silico tools predict benign outcome. The variant is located outside of any know functional domain or repeat (InterPro). No functional studies confirming an effect of this change on protein function have been published at the time of evaluation. The variant is present in the control population dataset gnomAD at a frequency of 0.00003 (8/245616 chrs tested), which does not exceed the maximal expected allele frequency for a pathogenic BRIP1 variant (0.00006). The variant has been reported in at least two BrC individuals without strong evidence for causality (Easton_2016; Jalkh_2017). The variant is cited as uncertain significance by reputable databases/clinical laboratories. Taken together, the variant was classified as a "Variant of Uncertain Significance (VUS)," until new information becomes available.
Invitae RCV000198324 SCV000255174 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1191 of the BRIP1 protein (p.Ile1191Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs761405340, ExAC 0.009%). This variant has been reported in individuals affected with breast cancer (PMID: 28202063, 26921362) and pancreatic cancer (PMID: 28767289). ClinVar contains an entry for this variant (Variation ID: 186989). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.

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