Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000736078 | SCV001424739 | likely pathogenic | RASopathy | 2020-07-01 | reviewed by expert panel | curation | The c.793G>C (p.Gly265Arg) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed as a de novo occurrence in one proband diagnosed with a RASopathy (PM6, PS4_Supporting; Laboratory for Molecular Medicine internal data, ClinVar SCV000061628.5). 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). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Gly265Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathy. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM1, PM2, PM6, PP2, PP3. |
| Laboratory for Molecular Medicine, |
RCV000037962 | SCV000061628 | likely pathogenic | Noonan syndrome | 2015-01-08 | criteria provided, single submitter | clinical testing | The p.Gly265Arg variant in BRAF has been identified by our laboratory in 1 indiv idual with Noonan syndrome and occurred de novo. The variant has not been identi fied in large population studies. The glycine (Gly) at position 265 in BRAF is h ighly conserved in mammals and evolutionarily distant species, though additional computational prediction tools do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to f ully establish its clinical significance, the p.Gly265Arg variant is likely path ogenic. |
| Institute for Genomic Medicine |
RCV000736078 | SCV000864316 | likely pathogenic | RASopathy | 2017-03-14 | criteria provided, single submitter | clinical testing | PM1, PM2, PP2 and PP3; This guanine to cytosine change in the BRAF gene at nucleotide position 793 (c.793G>C) leads to the substitution of a glycine for an arginine at amino acid position 265 (p.Gly265Arg) [NC_000007.13:g.140501279C>G, NM_004333.4:c.793G>C (p.Gly265Arg)]. The identified variant was not observed in a large genomic database of reportedly healthy individuals (gnomAD), occurs at a highly conserved amino acid position, is predicted to have deleterious impact on the BRAF protein as determined by multiple in silico algorithms, and is located within a protein domain of BRAF in which other alterations known to be associated with Noonan syndrome related disorders are clustered. This alteration meets ACMG guidelines for classification as a likely pathogenic variant. |
| Service de Génétique Moléculaire, |
RCV000037962 | SCV000965947 | uncertain significance | Noonan syndrome | no assertion criteria provided | clinical testing |