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Variant: NM_004333.4(BRAF):c.1741A>G (p.Asn581Asp)

CA279976

13979 (ClinVar)

Gene: BRAF
Condition: cardiofaciocutaneous syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: f2cf40e6-1706-4a5e-b2f8-b7b396ddbde2
Approved on: 2017-04-03
Published on: 2018-12-10

HGVS expressions

NM_004333.4:c.1741A>G
NM_004333.4(BRAF):c.1741A>G (p.Asn581Asp)
NM_001354609.1:c.1741A>G
NM_004333.5:c.1741A>G
NR_148928.1:n.2046A>G
ENST00000288602.10:c.1741A>G
ENST00000479537.5:n.25A>G
ENST00000496384.6:n.564A>G
ENST00000497784.1:n.1776A>G
NC_000007.14:g.140754187T>C
CM000669.2:g.140754187T>C
NC_000007.13:g.140453987T>C
CM000669.1:g.140453987T>C
NC_000007.12:g.140100456T>C
NG_007873.3:g.175578A>G
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Pathogenic

Met criteria codes 6
PS3 PP3 PP2 PM1 PM6_Strong PM2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.1741A>G (p.Asn581Asp) variant in BRAF has been reported in the literature as a non-maternity/paternity confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6_Strong; PMID 25463315). In vitro functional studies provide some evidence that the p.Asn581Asp variant may impact protein function (PS3; 19376813, 16474404). 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). Furthermore, this variant is located in the catalytic loop of BRAF (PM1; 16474404, 29493581). Computational prediction tools and conservation analysis suggest that the p.Asn581Asp 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_Strong, PS3.
Met criteria codes
PS3
In vitro functional studies provide some evidence that the p.N581D variant may impact protein function (PS3; 19376813, 16474404).
PP3
Computational prediction tools and conservation analysis suggest that the p.N581D 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
Furthermore, this variant is located in the catalytic loop of BRAF (PM1; 16474404, 29493581).
PM6_Strong
The p.N581D variant in BRAF has been reported in the literature as a non-maternity/paternity confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6_S; PMID 25463315).
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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