Submissions for variant NM_004333.6(BRAF):c.1785T>G (p.Phe595Leu)

dbSNP: rs121913341

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000522002	SCV000616396	pathogenic	RASopathy	2017-04-03	reviewed by expert panel	curation	The c.1785T>G (p.Phe595Leu) variant in BRAF has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 19206169, 18042262; GTR ID's: 26957, 21766; ClinVar SCV000203922.4, SCV000207755.12). The variant has also been identified in at least 2 independent occurences in patients with clinical features of a RASopathy (PS4_Supporting; APHP-Robert Debré internal data; GTR ID 28338). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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, 16439621). 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.Phe595Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PM2, PM1, PP2, PP3, PS4_Supporting.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154266	SCV000203922	likely pathogenic	Cardio-facio-cutaneous syndrome	2014-04-01	criteria provided, single submitter	clinical testing	The Phe595Leu variant in BRAF has been reported in the literature in one individ ual with clinical features of Cardio-facio-cutaneous syndrome (CFC; Rodriguez-Vi ciana 2006). This same amino acid change caused by a different DNA change (c.178 5T>A) has also been reported to have occurred de novo in an individual with clin ical features of CFC syndrome (Schulz 2008). In addition, this variant was not i dentified in either parent of a proband (LMM unpublished data). Computational pr ediction tools and conservation analyses suggest that the Phe595Leu variant may impact the protein. In summary, this variant is likely pathogenic, though additi onal studies are required to fully establish its clinical significance.
GeneDx	RCV000157825	SCV000207755	pathogenic	not provided	2021-11-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant has been reviewed and classified as pathogenic by the ClinGen RASopathy Expert Panel (Gelb et al., 2018); This variant is associated with the following publications: (PMID: 16439621, 18042262, 12068308, 32269299, 29752777, 33040082, 26582644, 30138938, 24957944, 15488754, 29493581, 15520807, 17603483, 23093928, 30977659, 32913992, 29084544, 19206169)
Revvity Omics, Revvity	RCV000157825	SCV002022614	pathogenic	not provided	2020-05-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154266	SCV002041673	pathogenic	Cardio-facio-cutaneous syndrome	2021-11-04	criteria provided, single submitter	clinical testing	Variant summary: BRAF c.1785T>G (p.Phe595Leu) results in a non-conservative amino acid change located in the Protein Kinase Domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251240 control chromosomes (gnomAD). c.1785T>G has been reported in the literature in multiple individuals affected with Cardiofaciocutaneous Syndrome (examples: Rodrigues-Viciana_2006, Sarkozy_2009, Yoon_2007, Pierpont_2010, Abe_2012, Alfieri_2013, Lee_2021). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000522002	SCV004294693	pathogenic	RASopathy	2023-07-28	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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: 177672). This missense change has been observed in individual(s) with BRAF-related conditions (PMID: 16439621, 29084544, 33040082, 33318624). In at least one individual the variant was observed to be de novo. This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 595 of the BRAF protein (p.Phe595Leu).
Database of Curated Mutations (DoCM)	RCV000445270	SCV000505586	likely pathogenic	Melanoma	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426478	SCV000505587	likely pathogenic	Neoplasm	2016-05-13	no assertion criteria provided	literature only
GenomeConnect - CFC International	RCV000522002	SCV001245248	not provided	RASopathy		no assertion provided	phenotyping only	Variant was identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 05-19-2015 by lab or GTR ID GeneDx. Variant interpreted as Pathogenic and reported on 11-05-2020 by lab or GTR ID Mayo Clinic. GenomeConnect - CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.