ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3651G>A (p.Trp1217Ter) (rs542698396)

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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 RCV000166368 SCV000217158 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: No disease association in small case-control study,Structural Evidence,Conflicting evidence
Color RCV000166368 SCV000912101 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-05 criteria provided, single submitter clinical testing
Counsyl RCV000662837 SCV000785695 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-11-02 criteria provided, single submitter clinical testing
GeneDx RCV000586366 SCV000779489 uncertain significance not provided 2017-09-18 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3651G>A at the cDNA level and p.Trp1217Ter (W1217X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA). This variant has not, to our knowledge, been reported in the literature as a germline pathogenic or benign variant. Due to the position of the variant, nonsense mediated decay is not expected to occur, but it might cause loss of normal protein function through protein truncation. The disrupted region at the end of the gene is not within any known functional domain. BRIP1 Trp1217Ter was observed at an allele frequency of 0.01% (1/10302) in individuals of African ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Based on currently available information, we consider RAD51D Gln319Ter to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586366 SCV000699725 uncertain significance not provided 2017-02-02 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.3651G>A (p.Trp1217X) variant results in a premature termination codon, however the termination codon is located toward the end of exon 20, the last exon of the gene. Additionally, there are literature reports that suggest the lack of breast cancer risk in carriers of truncating BRIP1 variants. Therefore, it is unclear what the functional effect of this truncated variant would result in. One in silico tool predicts a damaging outcome for this variant. This variant was found in 5/120938 control chromosomes at a frequency of 0.0000413, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625). One clinical diagnostic laboratory/reputable database classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Due to the location of this truncating variant and the unknown effect on protein function, it has been classified as a VUS until additional evidence becomes available.
Invitae RCV000457986 SCV000547254 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-06 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the BRIP1 gene (p.Trp1217*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 33 amino acids of the BRIP1 protein. This variant is present in population databases (rs542698396, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 186726). Experimental studies have not been reported for this truncating variant and it is currently unknown if the last 33 amino acids of the BRIP1 protein are critical for its function. 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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