Submissions for variant NM_001374258.1(BRAF):c.1523T>C (p.Phe508Ser)

dbSNP: rs397507473

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000033305	SCV000057210	pathogenic	not provided	2022-06-02	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 26150740, 23093928, 17551924, 24803665, 31263281, 16439621, 18042262, 24957944, 15488754, 15520807, 17603483)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037917	SCV000061579	pathogenic	Cardio-facio-cutaneous syndrome	2009-06-02	criteria provided, single submitter	clinical testing
Invitae	RCV000797502	SCV000937062	pathogenic	RASopathy	2021-12-01	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: 40366). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome or other RASopathy disorders (PMID: 16439621, 17551924, 18042262, 29084544). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs397507473, gnomAD 0.0009%). This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 468 of the BRAF protein (p.Phe468Ser).
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001293860	SCV001482525	pathogenic	Cardiofaciocutaneous syndrome 1	2021-02-19	criteria provided, single submitter	research	ACMG codes:PS2, PS4M, PM1, PM2, PP2, PP3, PP5
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813222	SCV002060517	pathogenic	Noonan syndrome and Noonan-related syndrome	2019-04-01	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000033305	SCV002502773	likely pathogenic	not provided	2021-10-20	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251944	SCV002523369	pathogenic	See cases	2019-11-29	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4, PM1, PM6, PP2, PP3
PreventionGenetics, part of Exact Sciences	RCV003407389	SCV004110177	pathogenic	BRAF-related condition	2023-02-24	criteria provided, single submitter	clinical testing	The BRAF c.1403T>C variant is predicted to result in the amino acid substitution p.Phe468Ser. This variant has been reported in at least six individuals with cardio-facio-cutaneous syndrome (Rodriguez-Viciana et al. 2006. PubMed ID: 16439621; Gripp et al. 2007. PubMed ID: 17551924; Nava et al. 2007. PubMed ID: 17704260; Schulz et al. 2007. PubMed ID: 18042262) and one individual with Noonan syndrome (Xu et al. 2017. PubMed ID: 29084544). In at least three individuals this variant occurred de novo (Gripp et al. 2007. PubMed ID: 17551924; Schulz et al. 2007. PubMed ID: 18042262). Additionally, different amino acid substitutions affecting the same (p.Phe468Cys) and adjacent (p.Ser467Ala, p.Gly469Arg, p.Gly469Glu) amino acids have been reported as pathogenic (Human Gene Mutation Database). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-140481405-A-G). This variant is interpreted as pathogenic.