Submissions for variant NM_004333.6(BRAF):c.254A>G (p.Tyr85Cys)

gnomAD frequency: 0.00001  dbSNP: rs1131691387

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588426	SCV000582024	uncertain significance	not provided	2017-05-08	criteria provided, single submitter	clinical testing	The Y85C variant in the BRAF gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The Y85C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y85C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, but in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret Y85C as a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588426	SCV000698338	uncertain significance	not provided	2016-07-11	criteria provided, single submitter	clinical testing	Variant summary: The BRAF c.254A>G (p.Tyr85Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). It has not been reported in any known protein domain in UniProt, Entrez gene, and Ensemble. This variant was absent in 121104 control chromosomes and has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant has currently been classified as a variant of uncertain significance (VUS) until additional information becomes available.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291648	SCV002584544	uncertain significance	Noonan syndrome 7	2022-08-10	criteria provided, single submitter	clinical testing	The BRAF c.254A>G (p.Tyr85Cys) missense change has a maximum subpopulation frequency of 0.0065% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002524027	SCV003264637	uncertain significance	RASopathy	2024-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 85 of the BRAF protein (p.Tyr85Cys). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with BRAF-related conditions. ClinVar contains an entry for this variant (Variation ID: 429447). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BRAF protein function with a positive predictive value of 95%. 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.
Ambry Genetics	RCV005298503	SCV005969251	uncertain significance	Cardiovascular phenotype	2024-12-25	criteria provided, single submitter	clinical testing	The c.254A>G (p.Y85C) alteration is located in exon 3 (coding exon 3) of the BRAF gene. This alteration results from a A to G substitution at nucleotide position 254, causing the tyrosine (Y) at amino acid position 85 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.