ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1760A>T (p.His587Leu) (rs876660646)

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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 RCV000216569 SCV000278250 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-17 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000219246 SCV000279642 uncertain significance not provided 2017-11-13 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1760A>T at the cDNA level, p.His587Leu (H587L) at the protein level, and results in the change of a Histidine to a Leucine (CAT>CTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 His587Leu was not observed in large population cohorts (Lek 2016). Since Histidine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BRIP1 His587Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000460900 SCV000547349 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-11-13 criteria provided, single submitter clinical testing This sequence change replaces histidine with leucine at codon 587 of the BRIP1 protein (p.His587Leu). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 233799). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000662901 SCV000785822 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-12-12 criteria provided, single submitter clinical testing
Color RCV000216569 SCV001347349 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194199 SCV001363546 uncertain significance not specified 2019-04-18 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.1760A>T (p.His587Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251434 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.1760A>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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