rs397516903
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3PP2PS4_SupportingPM1
This summary comes from the ClinGen Evidence Repository: The c.739T>G (p.Phe247Val) variant in BRAF has been identified in at least 2 independent occurrences in patients with clinical features of a RASopathy (PS4_Supporting; Partners LMM, GeneDx internal data; GTR Lab IDs 21766, 26957; ClinVar SCV000061624.5, SCV000330320.6). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.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, 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). A different pathogenic missense variant (p.Phe247Leu) has been previously identified at this codon of BRAF which may indicate that this residue is critical to the function of the protein (PM5 not usable due to PM1 application; ClinVar 180784, 55793). Computational prediction tools and conservation analysis suggest that the p.Phe247Val variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2, PM1, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA135140/MONDO:0021060/004
Frequency
Consequence
NM_001374258.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRAF | NM_001374258.1 | c.739T>G | p.Phe247Val | missense_variant | 6/20 | ENST00000644969.2 | |
BRAF | NM_004333.6 | c.739T>G | p.Phe247Val | missense_variant | 6/18 | ENST00000646891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRAF | ENST00000644969.2 | c.739T>G | p.Phe247Val | missense_variant | 6/20 | NM_001374258.1 | |||
BRAF | ENST00000646891.2 | c.739T>G | p.Phe247Val | missense_variant | 6/18 | NM_004333.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 01, 2021 | Not observed at significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Chen2021[review], 24957944, 15488754, 16439621, 15520807, 17603483, 29493581) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2022 | - - |
Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
Noonan syndrome and Noonan-related syndrome Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | May 10, 2019 | The c.739T>G (p.Phe247Val) variant in BRAF has been identified in at least 2 independent occurrences in patients with clinical features of a RASopathy (PS4_Supporting; Partners LMM, GeneDx internal data; GTR Lab IDs 21766, 26957; ClinVar SCV000061624.5, SCV000330320.6). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.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, 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). A different pathogenic missense variant (p.Phe247Leu) has been previously identified at this codon of BRAF which may indicate that this residue is critical to the function of the protein (PM5 not usable due to PM1 application; ClinVar 180784, 55793). Computational prediction tools and conservation analysis suggest that the p.Phe247Val variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2, PM1, PP2, PP3. - |
RASopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 24, 2022 | ClinVar contains an entry for this variant (Variation ID: 44830). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Phe247 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28512244, 33040082, 33128510; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRAF protein function. This missense change has been observed in individual(s) with clinical features of BRAF-related conditions (PMID: 31785789, 32005694). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 247 of the BRAF protein (p.Phe247Val). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 10, 2013 | The Phe247Val variant in BRAF has not been reported in the literature nor previo usly identified by our laboratory. Computational analyses (biochemical amino aci d properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide stron g support for or against an impact to the protein. In summary, additional inform ation is needed to fully asses the clinical significance of the Phe247Val varian t. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at