Submissions for variant NM_004333.6(BRAF):c.2135C>A (p.Ala712Asp)

dbSNP: rs727502904

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150197	SCV000197121	likely pathogenic	Noonan syndrome; Cardio-facio-cutaneous syndrome	2015-03-16	criteria provided, single submitter	clinical testing	The p.Ala712Asp variant in BRAF has been identified by our laboratory in 2 indiv iduals with Noonan syndrome including one de novo occurrence. It was absent from large population studies. Computational prediction tools and conservation analy sis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although addition al studies are required to fully establish its clinical significance, the p.Ala7 12Asp variant is likely pathogenic.
Blueprint Genetics	RCV000788373	SCV000927458	likely pathogenic	not provided	2017-10-31	criteria provided, single submitter	clinical testing
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV001374414	SCV001571369	likely pathogenic	Noonan syndrome 7	2021-04-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000788373	SCV002012567	pathogenic	not provided	2021-09-23	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224801	SCV003920898	likely pathogenic	Cardiofaciocutaneous syndrome 1; LEOPARD syndrome 3; Noonan syndrome 7; Melanoma, cutaneous malignant, susceptibility to, 1; Colorectal cancer; Lung cancer	2021-03-30	criteria provided, single submitter	clinical testing	BRAF NM_004333.4 exon 18 p.Ala712Asp (c.2135C>A): This variant has not been reported in the literature but was identified as de novo in one patient in our lab. It is not present in large control databases. This variant is present in ClinVar, with multiple labs classifying this variant as likely pathogenic (Variation ID:162795). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000824929	SCV000965961	likely pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing
Invitae	RCV001850036	SCV002274194	uncertain significance	RASopathy	2022-06-04	flagged submission	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 162795). This variant has not been reported in the literature in individuals affected with BRAF-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 712 of the BRAF protein (p.Ala712Asp).