ClinVar Miner

Submissions for variant NM_001374258.1(BRAF):c.995C>T (p.Thr332Ile) (rs1008080053)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780969 SCV000918667 likely benign not specified 2018-01-08 criteria provided, single submitter clinical testing Variant summary: The c.995C>T (p. Thr332Ile) in BRAF gene is a missense variant involves a conserved nucleotide and 3/5 in silico tools used predict benign outcome. The variant is located outside of any know functional domain or repeat, however no functional studies confirming an effect of this change on the protein function were published at the time of evaluation. The variant is present in the control population dataset of gnomAD (0.00002165; 6/277190 chrs tested), exclusively in individuals of European descent (0.000047; 6/126700 chrs tested). The individual frequencies exceed the maximal expected allele frequency for a disease causing allele in BRAF gene (0.0000047), suggesting that this variant may represent a rare ethnic polymorphism. The variant has not been reported in affected or cited by a reputable database/clinical laboratory. Taken together, the variant was classified as likely Benign, until new information becomes available.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV001543118 SCV001761632 uncertain significance Noonan syndrome 2021-07-22 criteria provided, single submitter clinical testing The BRAF c.995C>T (p.Thr332Ile) missense change has a maximum subpopulation frequency of 0.0046% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/7-140494253-G-A). This variant occurs in a gene where missense variants are a common mechanism of disease (PP2). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in individuals with RASopathy conditions. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria, as specified by the RASopathy Variant Curation Expert Panel (PMID:29493581): PP2, BP4.

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