ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.1781A>T (p.Asp594Val) (rs121913338)

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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 RCV000796335 SCV001424741 pathogenic Rasopathy 2020-05-18 reviewed by expert panel curation The c.1781A>T (p.Asp594Val) variant in BRAF was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant has been reported in 3 probands with clinical features of a RASopathy (PS4_Moderate; SCV000935844.1, SCV000965957.1, GeneDx internal data). In one proband, the variant was reported as de novo with confirmed parentage (PS2). The c.1781A>T (p.Asp594Val) variant is located in the CR3 activation segment of BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the variant may impact protein function (PP3). Finally, c.1781A>T (p.Asp594Val) 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). 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): PS2, PS4_Moderate, PM1, PM2, PP2, PP3,
Invitae RCV000796335 SCV000935844 uncertain significance Rasopathy 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 594 of the BRAF protein (p.Asp594Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with cardio-facio-cutaneous syndrome (PMID: 18413255). ClinVar contains an entry for this variant (Variation ID: 375946). This variant has been reported to affect BRAF protein function (PMID: 18413255, 20141835, 19376813, 19735675). 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.
Database of Curated Mutations (DoCM) RCV000421094 SCV000504289 pathogenic Neoplasm of the large intestine 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434803 SCV000504290 pathogenic Melanoma 2015-07-14 no assertion criteria provided literature only
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000824925 SCV000965957 uncertain significance Cardio-facio-cutaneous syndrome no assertion criteria provided clinical testing

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