ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2801T>C (p.Phe934Ser) (rs778916092)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204761 SCV000259636 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-09-25 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 934 of the BRIP1 protein (p.Phe934Ser). The phenylalanine residue is weakly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is present in population databases (rs778916092, ExAC 0.03%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 219645). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine 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 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.
Ambry Genetics RCV000221756 SCV000273620 likely benign Hereditary cancer-predisposing syndrome 2018-07-17 criteria provided, single submitter clinical testing Other strong data supporting benign classification;In silico models in agreement (benign)
Illumina Clinical Services Laboratory,Illumina RCV000282226 SCV000404586 uncertain significance Neoplasm of the breast 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000320950 SCV000404587 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.
Color RCV000221756 SCV000903271 likely benign Hereditary cancer-predisposing syndrome 2016-05-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192827 SCV001361202 uncertain significance not specified 2019-11-29 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.2801T>C (p.Phe934Ser) 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 4.8e-05 in 251368 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer (4.8e-05 vs 6.3e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2801T>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (2x likely benign, 2x VUS). Based on the evidence outlined above, the variant was classified as uncertain significance.

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