ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3104G>A (p.Arg1035His) (rs367816363)

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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 RCV000116152 SCV000184539 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000116152 SCV000912102 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-13 criteria provided, single submitter clinical testing
Counsyl RCV000662500 SCV000785023 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-03-27 criteria provided, single submitter clinical testing
GeneDx RCV000212333 SCV000150061 uncertain significance not provided 2017-09-08 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3104G>A at the cDNA level, p.Arg1035His (R1035H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has been identified in at least one individual with colon cancer whose tumor was microsatellite stable and/or had normal immunohistochemistry (Pearlman 2016). BRIP1 Arg1035His was observed at an allele frequency of 0.005% (3/66,740) in large population cohorts (Lek 2016, NHLBI Exome Sequencing Project). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. BRIP1 Arg1035His occurs at a position that is not conserved and is located in the BRCA1 binding domain (Cantor 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on the currently available information, we consider BRIP1 Arg1035His to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781175 SCV000919054 uncertain significance not specified 2018-06-15 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.3104G>A (p.Arg1035His) 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 allele was found at a frequency of 1.8e-05 in 277150 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.3104G>A, has been reported in the literature in an individual affected with Colon Cancer (Pearlman_2017). This report does not provide an unequivocal conclusion 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 CllinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000206801 SCV000262275 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1035 of the BRIP1 protein (p.Arg1035His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs367816363, ExAC 0.004%). This variant has been observed in individuals affected with breast and ovarian cancer, and colon cancer (PMID: 27978560, Invitae). However, in one of these individuals a pathogenic allele was also identified in BRIP1, which suggests that this c.3104G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 128183). 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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