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]

Variant: NM_004333.4(BRAF):c.735A>C (p.Leu245Phe)

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CA280027

40347 (ClinVar)

Gene: BRAF

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: cf6b44e4-40ca-4713-b35e-0ad194eb2f96

Approved on: 2019-05-10

Published on: 2019-06-28

HGVS expressions

NM_004333.4:c.735A>C

NM_004333.4(BRAF):c.735A>C (p.Leu245Phe)

NC_000007.14:g.140801537T>G

CM000669.2:g.140801537T>G

NC_000007.13:g.140501337T>G

CM000669.1:g.140501337T>G

NC_000007.12:g.140147806T>G

NG_007873.3:g.128228A>C

NM_001354609.1:c.735A>C

NM_004333.5:c.735A>C

NR_148928.1:n.1040A>C

ENST00000288602.10:c.735A>C

ENST00000497784.1:n.770A>C

Pathogenic

PP2 PP3 PM1 PM2 PS4_Supporting PS2_Very Strong

PS3 PS1 BP1 BP4 BP2 BP3 BP7 BP5 BA1 PP1 PM5 PM4 PM6 BS2 BS1 BS4 BS3

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.735A>C (p.Leu245Phe) variant in BRAF has been reported as a a de novo occurrence, one of which was confirmed in at least 4 patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, GeneDx University Magdeburg GTR Lab ID's 21766, 26957, 506381; ClinVar SCV000061622.5, SCV000057188.16 PMID 19416762). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Leu245Phe variant may impact the protein (PP3). 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). 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): PS2_VeryStrong, PM2, PM1, PP2, PP3, PS4_Supporting.

PP2

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).

PP3

Computational prediction tools and conservation analysis suggest that the p.Leu245Phe variant may impact the protein (PP3).

PM1

This variant is located in exon 6 which has been designated as a hot spot by the ClinGen RAS VCEP

PM2

This variant is absent from gnomAD

PS4_Supporting

GeneDx- de novo via whole exome (PS2) LMM- detected in 1 patient with CFC; no parental data Invitae-detected in 2 patients with clinical features of RASopathy Fulgent- identified in patient with motor and language delay (ID panel testing). Never got parental data Koudova 2009- de novo case.

PS2_Very Strong

This variant has been identified in 4 de novo occurrences one of which has been confirmed. GeneDx: de novo via whole exome sequencing. Koudova 19416762: p.Leu245Phe variant was detected in a patient with a RASopathy. Martin Zenker has confirmed that this patient had the c.735A>C change. Martin Zenker also stated that his laboratory has 2 further unpublished de novo cases with this particular variant.

PS3