Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_004333.6(BRAF):c.793G>C (p.Gly265Arg)

CA261666

44832 (ClinVar)

Gene: BRAF

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 36ccb1ce-1912-4c71-8267-399b17f45c37

Approved on: 2020-07-01

Published on: 2020-07-01

HGVS expressions

NM_004333.6:c.793G>C

NM_004333.6(BRAF):c.793G>C (p.Gly265Arg)

NM_004333.4:c.793G>C

NM_001354609.1:c.793G>C

NM_004333.5:c.793G>C

NR_148928.1:n.1098G>C

NM_001354609.2:c.793G>C

NM_001374244.1:c.793G>C

NM_001374258.1:c.793G>C

ENST00000288602.10:c.793G>C

ENST00000497784.1:n.828G>C

NC_000007.14:g.140801479C>G

CM000669.2:g.140801479C>G

NC_000007.13:g.140501279C>G

CM000669.1:g.140501279C>G

NC_000007.12:g.140147748C>G

NG_007873.3:g.128286G>C

Likely Pathogenic

PP2 PP3 PS4_Supporting PM1 PM2 PM6

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

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.

PP2

BRAF is a missense-constrained gene (PMID:29493581).

PP3

REVEL 0.917. Entirely conserved in UCSC database. Alamut does not predict an impact to splicing.

PS4_Supporting

Observed in 1 proband with Noonan syndrome.

PM1

Occurs in exon 6 of BRAF, which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID: 29493581).

PM2

Absent from both versions of gnomAD.

PM6

1 de novo case with Noonan syndrome.

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