ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.1595G>A (p.Cys532Tyr) (rs397507479)

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Total submissions: 5
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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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000080902 SCV000112809 likely pathogenic not provided 2017-08-29 criteria provided, single submitter clinical testing
GeneDx RCV000080902 SCV000057229 likely pathogenic not provided 2016-05-31 criteria provided, single submitter clinical testing The C532Y missense variant has not been previously reported as a pathogenic variant nor is it a known benign polymorphism. Another clinical laboratory has observed this variant as de novo (SCV000112809). The C532Y variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In silico analysis predicts this variant is probably damaging to the protein structure/function. C532Y is a non-conservative amino acid substitution as Tyrosine is a larger and bulkier polar residue than the normal Cysteine. Cys532 is highly conserved across species and the loss of a Cysteine residue is likely to affect disulfide bonding. Other pathogenic missense variants (W531C and G534R) have been reported in neighboring codons (Sarkozy et al., 2009, Rodriquez-Viciana et al., 2008).
Invitae RCV000521124 SCV000659072 uncertain significance Rasopathy 2017-07-24 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 532 of the BRAF protein (p.Cys532Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRAF-related disease. ClinVar contains an entry for this variant (Variation ID: 40380). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Laboratory for Molecular Medicine,Partners HealthCare 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

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