Submissions for variant NM_004333.6(BRAF):c.1796C>T (p.Thr599Ile)

dbSNP: rs121913375

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV001172273	SCV001335313	pathogenic	RASopathy	2020-03-24	reviewed by expert panel	curation	The c.1796C>T (p.Thr599Ille) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It has been reported as a de novo occurrence with parentage confirmed in 1 proband diagnosed with cardiofaciocutaneous syndrome (PS2, PS4_Supporting; PMID 30732632). This variant was also observed as a de novo occurrence without parentage confirmed in proband with phenotypic features of a RASopathy but no clinical diagnosis (PM6; GeneDx internal data, SCV000057239.11). The variant occurs in the CR3 activation domain of BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr599Ile 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, this variant has also been observed in association with somatic malignancies; however, analysis and classification of somatic variation is currently not used to inform germline classifications for the RASopathies. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy based on RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS4_Supporting, PM1, PM2, PM6, PP2, PP3.
GeneDx	RCV000033334	SCV000057239	pathogenic	not provided	2022-01-28	criteria provided, single submitter	clinical testing	Not observed 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: 33482860, 30732632, 24957944, 15488754, 16439621, 15520807, 17603483, 29493581)
Institute of Human Genetics, University of Leipzig Medical Center	RCV001705626	SCV001934482	likely pathogenic	Cardiofaciocutaneous syndrome 1	2021-03-15	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000433036	SCV000505585	likely pathogenic	Melanoma	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440873	SCV000510426	likely pathogenic	Neoplasm	2016-05-13	no assertion criteria provided	literature only
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000824927	SCV000965959	uncertain significance	Noonan syndrome		no assertion criteria provided	clinical testing