Submissions for variant NM_004333.6(BRAF):c.741T>G (p.Phe247Leu)

dbSNP: rs397509343

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000788009	SCV000927041	pathogenic	Noonan syndrome and Noonan-related syndrome	2019-05-10	reviewed by expert panel	curation	The c.741T>G (p.Phe247Leu) variant in BRAF has been reported in the literature as a confirmed and unconfirmed de novo occurrence in 2 patients with clinical features of a RASopathy (PM6, PS2, PS4_Supporting; GeneDx internal data; GTR Lab ID 26957; SCV000077236.10). In vitro functional studies provide some evidence that the p.Phe247Leu variant may impact protein function (PS3; PMID: 28512244). 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). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.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). 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, PS2, PS3, PM1, PM2, PP2, PP3, PS4_Supporting.
GeneDx	RCV000049222	SCV000077236	pathogenic	not provided	2023-07-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the variant promotes cell growth and activates MAPK signaling (Lu et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26243863, 31515458, 33726816, 35524774, 34184037, 35624529, 24957944, 15488754, 16439621, 15520807, 17603483, 29493581, 33040082, 27478437, 29533785, 28512244)
Invitae	RCV001384671	SCV001584243	pathogenic	RASopathy	2021-09-15	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. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 55793). This missense change has been observed in individuals with clinical features consistent with a RASopathy (PMID: 28512244; Invitae). This variant is not present in population databases (ExAC no frequency).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000049222	SCV004563413	pathogenic	not provided	2023-01-26	criteria provided, single submitter	clinical testing	The BRAF c.741T>G; p.Phe247Leu variant (rs397509343), is not reported in the medical literature in individuals with suspected RASopathy; however, this variant was confirmed de novo in an individual included in a cohort of rare diseases where specific phenotype information was not provided (Stranneheim 2021). This variant is reported in ClinVar (Variation ID: 55793) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. In vitro functional analyses demonstrate MAPK activation (Lu 2017) which is consistent with the established gain of function disease mechanism for BRAF-related disorders. Additionally, this variant occurs in a known functional domain (Gelb 2018) and other variants at this and neighboring codons (c.739T>C, p.Phe247Leu; c.736G>C, p.Ala246Pro) have been reported in individuals with BRAF-related disorders (Bertola 2020, Niihori 2006). Computational analyses predict that this variant is deleterious (REVEL: 0.816). Based on available information, the c.741T>G; p.Phe247Leu variant is considered to be pathogenic. References: Bertola DR et al. Phenotype-genotype analysis of 242 individuals with RASopathies: 18-year experience of a tertiary center in Brazil. Am J Med Genet C Semin Med Genet. 2020 Dec;184(4):896-911. PMID: 33128510. Gelb BD et al. ClinGen's RASopathy Expert Panel consensus methods for variant interpretation. Genet Med. 2018 Nov;20(11):1334-1345. PMID: 29493581. Lu H et al. Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer. Cancer Res. 2017 Jul 1;77(13):3502-3512. PMID: 28512244. Niihori T et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet. 2006 Mar;38(3):294-6. PMID: 16474404. Stranneheim H et al. Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients. Genome Med. 2021 Mar 17;13(1):40. PMID: 33726816.
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000824914	SCV000965945	likely pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing