ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.736G>C (p.Ala246Pro) (rs180177034)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208416 SCV000263793 pathogenic Cardio-facio-cutaneous syndrome 2015-01-23 criteria provided, single submitter clinical testing
ClinGen RASopathy Variant Curation Expert Panel RCV000208416 SCV000616359 pathogenic Cardio-facio-cutaneous syndrome 2017-04-03 reviewed by expert panel curation The c.736G>C (p.Ala246Pro) variant in BRAF has been reported in the literature as a de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6 and PS2; PMID 16474404 and 18042262). In vitro functional studies provide some evidence that the p.Ala246Pro variant may impact protein function (PS3; 16474404, 19376813). This variant was absent from large population studies (PM2; ExAC, http://exac.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). This variant is in a location which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Ala246Pro 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): PP2, PP3, PM1, PM2, PM6, PS2, PS3.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678900 SCV000805097 pathogenic Noonan syndrome 2017-06-15 no assertion criteria provided clinical testing
GeneDx RCV000235118 SCV000057190 pathogenic not provided 2018-01-09 criteria provided, single submitter clinical testing The A246P missense variant in the BRAF gene has been reported previously in association with Cardio-Facio-Cutaneous (CFC) syndrome and observed de novo in multiple patients (Niihori et al., 2006; Schulz et al., 2008; Croonen et al. 2013). The variant is not observed in large population cohorts (Lek et al., 2016). Functional in vitro studies demonstrated that the A246P variant results in increased ELK-dependent transcription, leading to activation of BRAF and stimulation of downstream effectors (MEK and ERK) (Niihori et al., 2006). Missense variants in nearby residues (T241P/M/R, T244P, L245F) have been reported in the Human Gene Mutation Database in association with Noonan spectrum disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000033285 SCV000203919 pathogenic Noonan syndrome; Cardio-facio-cutaneous syndrome 2013-08-02 criteria provided, single submitter clinical testing The p.Ala246Pro variant in BRAF has been reported in 6 individuals with clinical features of Cardio-facio-cutaneous syndrome (CFC) (Niihori 2006, Nava 2007, Nys trom 2008, Schulz 2008, Ohtake 2011). This variant occurred de novo in 2 of thes e individuals (Niihori 2006, Schulz 2008), and one of these individuals also had Non-Hodgkin Lymphoma (Ohtake 2011). Furthermore, this variant has now been iden tified by our laboratory in 5 individuals with clinical features of Noonan syndr ome and/or CFC syndrome. It was also absent from large population studies. There fore, this variant meets our criteria to be classified as pathogenic (http://www .partners.org/personalizedmedicine/LMM).
OMIM RCV000014998 SCV000035254 pathogenic Cardiofaciocutaneous syndrome 1 2006-03-01 no assertion criteria provided literature only

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