rs397516905
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM6PM2PP3PP2PS4_SupportingPM1
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA261666/MONDO:0021060/004
Frequency
Consequence
NM_001374258.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRAF | NM_001374258.1 | c.793G>C | p.Gly265Arg | missense_variant | 6/20 | ENST00000644969.2 | |
BRAF | NM_004333.6 | c.793G>C | p.Gly265Arg | missense_variant | 6/18 | ENST00000646891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRAF | ENST00000644969.2 | c.793G>C | p.Gly265Arg | missense_variant | 6/20 | NM_001374258.1 | |||
BRAF | ENST00000646891.2 | c.793G>C | p.Gly265Arg | missense_variant | 6/18 | NM_004333.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
RASopathy Pathogenic:2
Likely pathogenic, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Jul 01, 2020 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital | Mar 14, 2017 | 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. - |
Noonan syndrome Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 08, 2015 | 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at