rs794729219
Variant summary
Our verdict is Pathogenic. Variant got 27 ACMG points: 27P and 0B. PS1_Very_StrongPM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001374258.1(BRAF):c.1903T>C(p.Phe635Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F635S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001374258.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 27 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRAF | NM_001374258.1 | c.1903T>C | p.Phe635Leu | missense_variant | 16/20 | ENST00000644969.2 | |
BRAF | NM_004333.6 | c.1783T>C | p.Phe595Leu | missense_variant | 15/18 | ENST00000646891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRAF | ENST00000644969.2 | c.1903T>C | p.Phe635Leu | missense_variant | 16/20 | NM_001374258.1 | |||
BRAF | ENST00000646891.2 | c.1783T>C | p.Phe595Leu | missense_variant | 15/18 | NM_004333.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cardiofaciocutaneous syndrome 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Mendelics | Nov 06, 2013 | - - |
Cardio-facio-cutaneous syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 31, 2022 | Variant summary: BRAF c.1783T>C (p.Phe595Leu) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251240 control chromosomes (gnomAD). c.1783T>C has been reported in the literature in individuals affected with Cardiofaciocutaneous Syndrome (Ciara_2015, Matalon_2021), and in one case the de novo occurrence of the variant was confirmed. In addition two equivalent missense variants (c.1785T>A (p.F595L) and c.1785T>G (p.F595L)) have also been reported in patients affected with Cardio-facio-cutaneous syndrome (HGMD). These data indicate that the variant is likely associated with disease. Multiple publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in low to intermediate Braf kinase activity, which works cooperatively with Ras leading to increased MEK/ERK signaling (Kordes_2016, Yao_2017, Ng_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant in the germline state to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Melanoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 11, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(F594L); This variant is associated with the following publications: (PMID: 22142829, 24803665, 37039257, 33683002, 28856074, 34573299, 31060855, 32913992, 18039235, MelchorL2015[Abstract], 31573083, 33128510, 29533785, 19206169, 20186801, 18042262, 21871821, 22495831, 29084544, 23093928, 35226061, 33198372, 34331515, 36448195, 26826419, 37530550, 26582644, 16439621, 15035987, 25463315, 24957944, 15488754, 15520807, 17603483, 29493581) - |
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 595 of the BRAF protein (p.Phe595Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardio-facio-cutaneous (CFC) syndrome (PMID: 16439621, 18042262, 19206169, 20186801, 21871821, 22495831, 23093928, 25463315, 29084544). In at least one individual the variant was observed to be de novo. This variant is also known as F594L. ClinVar contains an entry for this variant (Variation ID: 202193). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt BRAF function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRAF function (PMID: 26582644). For these reasons, this variant has been classified as Pathogenic. - |
Prostate cancer, hereditary, 1 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Virology, Oncology, Biosciences and Environment, Faculty of Sciences and Techniques, Mohammedia- University Hassan II of Casablanca | Jul 29, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at