Evidence Repository
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.739T>C (p.Phe247Leu)

CA295904

180784 (ClinVar)

Gene: BRAF
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 9a18dc91-2016-4b25-ab42-a9f679412ae8
Approved on: 2019-05-10
Published on: 2019-06-28

HGVS expressions

NM_004333.4:c.739T>C
NM_004333.4(BRAF):c.739T>C (p.Phe247Leu)
NC_000007.14:g.140801533A>G
CM000669.2:g.140801533A>G
NC_000007.13:g.140501333A>G
CM000669.1:g.140501333A>G
NC_000007.12:g.140147802A>G
NG_007873.3:g.128232T>C
NM_001354609.1:c.739T>C
NM_004333.5:c.739T>C
NR_148928.1:n.1044T>C
ENST00000288602.10:c.739T>C
ENST00000497784.1:n.774T>C
More

Pathogenic

Met criteria codes 7
PM1 PM2 PM6 PS3 PS1 PP2 PP3
Not Met criteria codes 16
BA1 PM4 PM5 BS2 BS1 BS3 BS4 BP2 BP3 BP1 BP4 BP5 BP7 PS2 PS4 PP1

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.739T>C (p.Phe247Leu) variant in BRAF has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; GeneDx internal data; GTR Lab ID: 26957; ClinVar SCV000207748.12). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Phe247Leu variant may impact protein function (PS3; PMID: 28512244). The c.739T>C variant results in the same amino acid change as the previously established pathogenic c.741T>G (p.Phe247Leu) variant (PS1; ClinVar ID 55793). 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). 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). Computational prediction tools and conservation analysis suggest that the p.Phe247Leu 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): PM6, PM2, PS3, PS1, PM1, PP2, PP3.
Met criteria codes
PM1
Variant is located in exon 6 of BRAF, has been defined as hotspot by RAS VCEP
PM2
Variant is absent from gnomAD
PM6
GeneDx: identified variant in fetal sample with cystic hygroma and increased NT of 5.3mm
PS3
Variant alters the RAS MAPK pathway
Expression of the F247L variant robustly activated the MAPK pathway and sensitized cells to BRAF and MEK inhibitors. PubMed:28512244
PS1
The c.741T>G variant is pathogenic and also meets PS1 because this variant is Pathogenic even without PS1
PP2
Variant is in BRAF
PP3
REVEL score of 0.902
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
only case is the GeneDx patient, fetal sample wiht cystic hygroma and icnreased NT of 5.3mm
Variant has been identified in a hypermutated no MLH1 silenced Tumor in Donehower et al. 2013. Do not count PubMed:22899370
Variant was identified in colorectal cancer paper but the co-occurring HER2 variants were the ones that were functionally assessed. PubMed:26243863
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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