ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2285G>A (p.Arg762His) (rs200960251)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164605 SCV000215266 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-11 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000590146 SCV000279243 uncertain significance not provided 2018-01-11 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2285G>A at the cDNA level, p.Arg762His (R762H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant was observed in an individual undergoing multigene cancer panel testing based on a history of a Lynch-related cancer and/or polyps (Yurgelun 2015). BRIP1 Arg762His was observed at an allele frequency of 0.02% (6/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the helicase domain (Cantor 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Arg762His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000227922 SCV000291009 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 762 of the BRIP1 protein (p.Arg762His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs200960251, ExAC 0.02%). This variant has been reported in an individual affected with suspected Lynch syndrome (PMID: 25980754) and individuals affected with breast cancer (PMID: 26921362, 29368626). ClinVar contains an entry for this variant (Variation ID: 185226). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Color RCV000164605 SCV000684202 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855584 SCV000699687 uncertain significance not specified 2019-03-28 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.2285G>A (p.Arg762His) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7e-05 in 258673 control chromosomes, predominantly at a frequency of 0.00019 within the South Asian subpopulation in the gnomAD database, which is approximately 3 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this variant is possibly a benign polymorphism found in South Asian origin. The variant, c.2285G>A has been reported in the literature in individuals affected with breast cancer and in an individual with suspected Lynch syndrome (Easton_2016, Weber-Lassalle_2018, Yurgelun_2015). These reports however, 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. Seven 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 VUS-possibly benign.
Counsyl RCV000663145 SCV000786293 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2018-04-12 criteria provided, single submitter clinical testing
GeneKor MSA RCV000164605 SCV000821958 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590146 SCV000889212 uncertain significance not provided 2018-02-27 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001122086 SCV001280773 uncertain significance Fanconi anemia, complementation group J 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Leiden Open Variation Database RCV000590146 SCV001364468 uncertain significance not provided 2019-08-13 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.

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