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

  • See Evidence submitted by expert panel for details.

Variant: NM_004333.4(BRAF):c.736G>C (p.Ala246Pro)

CA279968

13965 (ClinVar)

Gene: BRAF
Condition: cardiofaciocutaneous syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 2eac9953-9576-4ab4-8bd3-c9d0c1d40f0c
Approved on: 2017-04-03
Published on: 2018-12-10

HGVS expressions

NM_004333.4:c.736G>C
NM_004333.4(BRAF):c.736G>C (p.Ala246Pro)
NC_000007.14:g.140801536C>G
CM000669.2:g.140801536C>G
NC_000007.13:g.140501336C>G
CM000669.1:g.140501336C>G
NC_000007.12:g.140147805C>G
NG_007873.3:g.128229G>C
NM_001354609.1:c.736G>C
NM_004333.5:c.736G>C
NR_148928.1:n.1041G>C
ENST00000288602.10:c.736G>C
ENST00000497784.1:n.771G>C
More

Pathogenic

Met criteria codes 7
PS2 PS3 PP3 PP2 PM1 PM2 PM6

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.736G>C (p.Ala246Pro) variant in BRAF has been reported in the literature as a de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6 and PS2; PMID 16474404 and 18042262). In vitro functional studies provide some evidence that the p.Ala246Pro variant may impact protein function (PS3; 16474404, 19376813). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). This variant is in a location which 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.Ala246Pro variant may impact the protein (PP3). 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): PP2, PP3, PM1, PM2, PM6, PS2, PS3.
Met criteria codes
PS2
The p.A246P variant in BRAF has been reported in the literature as a de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6 and PS2; PMID 16474404 and 18042262)
PS3
In vitro functional studies provide some evidence that the p.A246P variant may impact protein function (PS3; 16474404, 19376813).
PP3
Computational prediction tools and conservation analysis suggest that the p.A246P variant may impact the protein (PP3).
PP2
The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581).
PM1
his variant is in a location which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581).
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
The p.A246P variant in BRAF has been reported in the literature as a de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6 and PS2; PMID 16474404 and 18042262)
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.