Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
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 | 2018-12-15 | criteria provided, single submitter | clinical testing | 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. This variant has been reported to affect BRAF protein function (PMID: 18413255, 20141835, 19376813, 19735675). 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 is not present in population databases (ExAC no frequency). 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. |
| Database of Curated Mutations |
RCV000421094 | SCV000504289 | pathogenic | Neoplasm of the large intestine | 2014-10-02 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000434803 | SCV000504290 | pathogenic | Melanoma | 2015-07-14 | no assertion criteria provided | literature only | |
| Service de Génétique Moléculaire, |
RCV000824925 | SCV000965957 | uncertain significance | Cardio-facio-cutaneous syndrome | no assertion criteria provided | clinical testing |