ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.735A>C (p.Leu245Phe) (rs397507466)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000788013 SCV000927045 pathogenic Noonan syndrome and Noonan-related syndrome 2019-05-10 reviewed by expert panel curation The c.735A>C (p.Leu245Phe) variant in BRAF has been reported as a a de novo occurrence, one of which was confirmed in at least 4 patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, GeneDx University Magdeburg GTR Lab ID's 21766, 26957, 506381; ClinVar SCV000061622.5, SCV000057188.16 PMID 19416762). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Leu245Phe variant may impact the protein (PP3). 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). 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). 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): PS2_VeryStrong, PM2, PM1, PP2, PP3, PS4_Supporting.
Fulgent Genetics,Fulgent Genetics RCV000515291 SCV000611176 likely pathogenic Cardiofaciocutaneous syndrome 1; Lung cancer; Noonan syndrome 1; LEOPARD syndrome 3; Noonan syndrome 7 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000033283 SCV000057188 pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing The L245F variant has been published previously in association with Noonan spectrum disorders, including as an apparently de novo occurrence (Koudova et al., 2009; Sarkozy et al., 2009). It has also been confirmed to occur de novo in an individual sent to GeneDx for testing. The variant is not observed in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. A different nucleotide change leading to the same missense variant (c.735 A>T) as well as missense variants in nearby residues (T241P/R/M, T244P, A246P) have been reported in the Human Gene Mutation Database in association with cardio-facio-cutaneous syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider the variant to be pathogenic.
Invitae RCV000469440 SCV000553831 pathogenic Rasopathy 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 245 of the BRAF protein (p.Leu245Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This missense change and a different variant (c.735A>T) giving rise to the same protein effect observed here (p.Leu245Phe) have been observed in individuals affected with BRAF-related conditions (PMID: 19206169, 22190897, 30290804), including one individual in whom the variant was de novo (PMID: 19416762). ClinVar contains an entry for this variant (Variation ID: 40347). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037956 SCV000061622 likely pathogenic Cardio-facio-cutaneous syndrome 2010-06-24 criteria provided, single submitter clinical testing
OMIM RCV000171142 SCV000223706 pathogenic LEOPARD syndrome 3 2009-09-01 no assertion criteria provided literature only

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