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

dbSNP: rs397507466

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000788012	SCV000927044	pathogenic	Noonan syndrome and Noonan-related syndrome	2019-05-10	reviewed by expert panel	curation	The c.735A>T p.Leu245Phe variant in BRAF has been identified in at least 2 independent occurrences, one of which was de novo, in patients with clinical features of a RASopathy (PM6, PS4_Supporting; Partners LMM, University Magdeburg internal data; GTR Lab IDs: 21766, 506381 PMID: 19206169, 22190897). 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). Of note, the p.Leu245Phe change has also been reported as a consequence of the c.735A>C variant in BRAF, which has been classified as pathogenic and therefore supports that this residue may be critical to protein function (PS1; ClinVar ID: 40347). 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): PS4_Supporting, PM6, PM1, PM2, PS1, PP2, PP3.
GeneDx	RCV000033284	SCV000057189	pathogenic	not provided	2012-03-28	criteria provided, single submitter	clinical testing	The L245F missense mutation in the BRAF gene has been published previously in association with Cardio-Facio-Cutaneous (CFC) Syndrome (Sarkozy et al., 2009). It has also been reported in an individual with LEOPARD syndrome and normal intelligence (Koudova et al., 2009). L245F results in a non-conservative amino acid substitution in that a small, compact Leucine residue is replaced with a large, bulky Phenylalanine at a position that is highly conserved. The variant is found in NOONAN panel(s).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037957	SCV000061623	likely pathogenic	Cardio-facio-cutaneous syndrome	2012-08-22	criteria provided, single submitter	clinical testing	The Leu245Phe variant in BRAF has been previously identified in the literature i n two patients, one with clinical features of Cardio-Facio-Cutaneous Syndrome an d one with clinical features of Leopard Syndrome, and was shown to be absent fro m 600 control chromosomes (Sarkozy 2009, Koudova 2009). This variant has been pr eviously identified by our laboratory in a single patient with clinical features of Noonan Syndrome but the nucleotide change differs (c.735A>C). In one patient , the variant was shown to have occured de novo (Koudova 2009). Moreover, this v ariant has not been identified in large and broad populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Computational analyses ( biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summa ry, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688777	SCV000816401	likely pathogenic	RASopathy	2018-07-27	criteria provided, single submitter	clinical testing	A different variant (c.735A>C) giving rise to the same protein effect observed here (p.Leu245Phe) has been reported in an individual affected with cardio-facio-cutaneous syndrome (PMID: 19416762), indicating that this residue may be critical for protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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"). This variant has been observed in individuals affected with cardio-facio-cutaneous syndrome (PMID: 19206169, 22190897). ClinVar contains an entry for this variant (Variation ID: 40348). This variant is not present in population databases (ExAC no frequency). 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.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002273939	SCV002558934	pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
GeneReviews	RCV000055897	SCV000086905	not provided	Noonan syndrome with multiple lentigines		no assertion provided	literature only