ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.739T>C (p.Phe247Leu) (rs397516903)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000788010 SCV000927042 pathogenic Noonan syndrome and Noonan-related syndrome 2019-05-10 reviewed by expert panel curation The c.739T>C (p.Phe247Leu) variant in BRAF has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; GeneDx internal data; GTR Lab ID: 26957; ClinVar SCV000207748.12). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Phe247Leu variant may impact protein function (PS3; PMID: 28512244). The c.739T>C variant results in the same amino acid change as the previously established pathogenic c.741T>G (p.Phe247Leu) variant (PS1; ClinVar ID 55793). 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). 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, PM2, PS3, PS1, PM1, PP2, PP3.
GeneDx RCV000157818 SCV000207748 pathogenic not provided 2018-11-29 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. An F247L variant in the BRAF gene resulting from a different nucleotide substitution (c.741 T>G) has been observed at GeneDx as a confirmed de novo pathogenic variant in a patient with features of a RASopathy. The F247L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F247L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position in the zinc finger/phorbolester domain that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (A246P, Q257R) have been found to activate ELK-dependent transcription, suggesting a contribution to BRAF activation (Niihori et al., 2006). In summary, this variant is pathogenic.
Invitae RCV000809145 SCV000949286 pathogenic Rasopathy 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 247 of the BRAF protein (p.Phe247Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual with clinical features consistent with a Rasopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 180784). Experimental in vitro studies have shown that cells transfected with this missense change show an increase in growth as well as in downstream MAPK signaling when compared to wild type (PMID: 28512244). For these reasons, this variant has been classified as Pathogenic.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000824913 SCV000965944 likely pathogenic Noonan syndrome no assertion criteria provided clinical testing

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