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

dbSNP: rs397507466

Total submissions: 7

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.
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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037956	SCV000061622	likely pathogenic	Cardio-facio-cutaneous syndrome	2010-06-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469440	SCV000553831	pathogenic	RASopathy	2022-06-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRAF protein function. ClinVar contains an entry for this variant (Variation ID: 40347). This missense change has been observed in individual(s) with clinical features of BRAF-related conditions (PMID: 19206169, 22190897, 30290804; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 245 of the BRAF protein (p.Leu245Phe).
Fulgent Genetics, Fulgent Genetics	RCV000515291	SCV000611176	likely pathogenic	Cardiofaciocutaneous syndrome 1; Lung carcinoma; Noonan syndrome 1; LEOPARD syndrome 3; Noonan syndrome 7	2017-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037956	SCV001467792	pathogenic	Cardio-facio-cutaneous syndrome	2020-12-28	criteria provided, single submitter	clinical testing	Variant summary: BRAF c.735A>C (p.Leu245Phe) results in a non-conservative amino acid change located in the phorbol ester/diacylglycerol-binding domain (IPR002219) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250260 control chromosomes (gnomAD). c.735A>C has been reported in the literature as a de novo variant in multiple individuals affected with Cardiofaciocutaneous Syndrome and related phenotypes belonging to the RASopathy spectrum (Koudova_2009, Pekeles_2019, Chinton_2019). In addition, a different variant resulting in the same missense change (c.735A>T (p.Leu245Phe)) has been reported in affected individuals (HGMD). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters, including an expert panel (ClinGen RASopathy Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (3x, including the expert panel) or likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000171142	SCV000223706	pathogenic	LEOPARD syndrome 3	2009-09-01	no assertion criteria provided	literature only