ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.741T>G (p.Phe247Leu) (rs397509343)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000788009 SCV000927041 pathogenic Noonan syndrome and Noonan-related syndrome 2019-05-10 reviewed by expert panel curation The c.741T>G (p.Phe247Leu) variant in BRAF has been reported in the literature as a confirmed and unconfirmed de novo occurrence in 2 patients with clinical features of a RASopathy (PM6, PS2, PS4_Supporting; GeneDx internal data; GTR Lab ID 26957; SCV000077236.10). In vitro functional studies provide some evidence that the p.Phe247Leu variant may impact protein function (PS3; PMID: 28512244). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe247Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PS2, PS3, PM1, PM2, PP2, PP3, PS4_Supporting.
GeneDx RCV000049222 SCV000077236 pathogenic not provided 2016-04-20 criteria provided, single submitter clinical testing The F247L pathogenic variant in the BRAF gene has been reported previously as a co-occurrence with a HER2 gene variant in a colorectal tumor sample (Kavuri et al., 2015). However, constitutional genetic testing was not performed to determine if the F247L variant was somatic, and therefore only present in the tumor, or if it was present in the germline. The F247L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The F247L variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (T244P, L245F, A246P) have been reported in the Human Gene Mutation Database in association with BRAF-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret F247L as a pathogenic variant
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000824914 SCV000965945 likely pathogenic Noonan syndrome no assertion criteria provided clinical testing

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