Submissions for variant NM_004333.6(BRAF):c.995C>T (p.Thr332Ile)

gnomAD frequency: 0.00004  dbSNP: rs1008080053

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780969	SCV000918667	likely benign	not specified	2018-01-08	criteria provided, single submitter	clinical testing	Variant summary: The c.995C>T (p. Thr332Ile) in BRAF gene is a missense variant involves a conserved nucleotide and 3/5 in silico tools used predict benign outcome. The variant is located outside of any know functional domain or repeat, however no functional studies confirming an effect of this change on the protein function were published at the time of evaluation. The variant is present in the control population dataset of gnomAD (0.00002165; 6/277190 chrs tested), exclusively in individuals of European descent (0.000047; 6/126700 chrs tested). The individual frequencies exceed the maximal expected allele frequency for a disease causing allele in BRAF gene (0.0000047), suggesting that this variant may represent a rare ethnic polymorphism. The variant has not been reported in affected or cited by a reputable database/clinical laboratory. Taken together, the variant was classified as likely Benign, until new information becomes available.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001543118	SCV001761632	uncertain significance	Noonan syndrome	2021-07-22	criteria provided, single submitter	clinical testing	The BRAF c.995C>T (p.Thr332Ile) missense change has a maximum subpopulation frequency of 0.0046% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/7-140494253-G-A). This variant occurs in a gene where missense variants are a common mechanism of disease (PP2). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in individuals with RASopathy conditions. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria, as specified by the RASopathy Variant Curation Expert Panel (PMID:29493581): PP2, BP4.
Invitae	RCV001856191	SCV002208335	uncertain significance	RASopathy	2023-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 332 of the BRAF protein (p.Thr332Ile). This variant is present in population databases (no rsID available, gnomAD 0.005%). 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: 633085). 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 not expected to disrupt BRAF protein function. 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.