ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.1595G>A (p.Cys532Tyr)

dbSNP: rs397507479
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000521124 SCV000616393 likely pathogenic RASopathy 2017-04-03 reviewed by expert panel curation The c.1595G>A (p.Cys532Tyr) variant in BRAF has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; Partners LMM, GeneDx, EGL internal data; GTR ID's: 21766, 26957, 500060; SCV000112809.7, SCV000057229.13, SCV000197143.4). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). Computational prediction tools and conservation analysis suggest that the p.Cys532Tyr variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PM2, PP2, PP3.
GeneDx RCV000080902 SCV000057229 likely pathogenic not provided 2024-07-03 criteria provided, single submitter clinical testing Reported in two individuals with neurodevelopmental disorders from large cohort studies, including one individual in which the variant occurred de novo, but detailed clinical information was not provided on these individuals (PMID: 31785789, 33004838); Reported in an abstract by Spencer et al. (2016) in an individual with features of cardio-facio-cutaneous syndrome, but familial segregation information was not provided Spencer et al. (2016) British Journal of Dermatology. 174:e24e31; Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; 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: 27478437, 29493581, 33004838, 31785789, 33057194, 35982159)
Eurofins Ntd Llc (ga) RCV000080902 SCV000112809 likely pathogenic not provided 2017-08-29 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000150205 SCV000197143 likely pathogenic Cardio-facio-cutaneous syndrome 2017-07-28 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Labcorp Genetics (formerly Invitae), Labcorp RCV000521124 SCV000659072 likely pathogenic RASopathy 2022-05-13 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 532 of the BRAF protein (p.Cys532Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRAF-related conditions (PMID: 31785789; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40380). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.