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.735A>T (p.Leu245Phe)

CA280029

40348 (ClinVar)

Gene: BRAF
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: fc4fa86e-060f-49dc-8ade-c259aa8ad24b
Approved on: 2019-05-10
Published on: 2019-06-28

HGVS expressions

NM_004333.4:c.735A>T
NM_004333.4(BRAF):c.735A>T (p.Leu245Phe)
NC_000007.14:g.140801537T>A
CM000669.2:g.140801537T>A
NC_000007.13:g.140501337T>A
CM000669.1:g.140501337T>A
NC_000007.12:g.140147806T>A
NG_007873.3:g.128228A>T
NM_001354609.1:c.735A>T
NM_004333.5:c.735A>T
NR_148928.1:n.1040A>T
ENST00000288602.10:c.735A>T
ENST00000497784.1:n.770A>T
More

Pathogenic

Met criteria codes 7
PS4_Supporting PS1 PP2 PP3 PM2 PM6 PM1
Not Met criteria codes 15
BS2 BS1 BS3 BS4 BP5 BP7 BP2 BP1 BP4 BP3 PS3 PS2 PP1 BA1 PM4

Evidence Links 4

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.735A>T p.Leu245Phe variant in BRAF has been identified in at least 2 independent occurrences, one of which was de novo, in patients with clinical features of a RASopathy (PM6, PS4_Supporting; Partners LMM, University Magdeburg internal data; GTR Lab IDs: 21766, 506381 PMID: 19206169, 22190897). 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). Of note, the p.Leu245Phe change has also been reported as a consequence of the c.735A>C variant in BRAF, which has been classified as pathogenic and therefore supports that this residue may be critical to protein function (PS1; ClinVar ID: 40347). 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): PS4_Supporting, PM6, PM1, PM2, PS1, PP2, PP3.
Met criteria codes
PS4_Supporting
LMM: Patient with Noonan syndrome was found to have this c.735A>T p.Leu245Phe variant. The parents were not sequenced. GeneDx: observed in one case, no detailed pheno information Invitae: c.735A>T variant detected in female in 30's with short stature. No further phenotypic information SarkozyDiglio: identified one pateint with CFC PMID: 19206169, 22190897.
p.Leu245Phe variant was identified in this melanoma cohort, but this should not be counted for Mendelian inheritance of RASopathies. PubMed:30820351
This patient is likely the same patient described in Digilio et al. 2011 because there is a substantial amount of author overlap between these two papers. PubMed:19206169
This group identified a patient who was 24 years old who had Noonan syndrome and the p.Leu245Phe change. However this variant is actually the c.735A>C change and therefore cannot be scored here. PubMed:23763990
Identified one patient with CFC with this variant. This study sequenced 134 patients with clinical features fitting the RASopathy spectrum. Patients were screened for PTPN11, SOS1, RAF1, KRAS, NRAS, SHOC2, CBL, BRAF, MEK1, MEK2, and HRAS variants PubMed:22190897
PS1
Assessed c.735A>C variant in BRAF. was confirmed to be pathogenic
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).
PM2
This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org).
PM6
Martin Zenker University of Magdeburg, Germany: one de novo case of this variant with NS.
PM1
Variant is in exon 6 of BRAF and therefore meets PM1.
Not Met criteria codes
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
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
BP2
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
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
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.