ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1246C>T (p.Arg416Trp) (rs587780225)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000571154 SCV000673151 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000571154 SCV000909785 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing
GeneDx RCV000116119 SCV000150028 uncertain significance not provided 2014-01-08 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1246C>T at the cDNA level, p.Arg416Trp (R416W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Arg416Trp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution, altering a position that is only moderately conserved throughout evolution and is located in the Helicase ATP-binding domain. In silico analyses predict this variant to have a benign effect on protein structure and function. Based on the currently available information, we consider BRIP1 Arg416Trp to be a variant of uncertain significance. Furthermore, BRIP1 has been only recently described in association with cancer predisposition and the risks are not well understood.
Integrated Genetics/Laboratory Corporation of America RCV000780058 SCV000917079 uncertain significance not specified 2018-05-07 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.1246C>T (p.Arg416Trp) results in a non-conservative amino acid change located in the Helicase superfamily 1/2, ATP-binding domain, DinG/Rad3-type and Helicase-like, DEXD box c2 type domain of 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 2e-05 in 245884 control chromosomes. This frequency is not higher than expected for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer (2e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.1246C>T has been reported in the literature in one individual affected with Hereditary Breast and Ovarian Cancer. This report 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000558154 SCV000633544 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2017-05-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 416 of the BRIP1 protein (p.Arg416Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs587780225, ExAC 0.006%) but has not been reported in the literature in individuals with a BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 128152). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tryptophan 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. 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.

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