chr7-140781603-C-G
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.1525G>C(p.Gly509Arg) 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. 12/19 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 Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G509E) has been classified as 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.1525G>C | p.Gly509Arg | missense_variant | 12/20 | ENST00000644969.2 | |
BRAF | NM_004333.6 | c.1405G>C | p.Gly469Arg | missense_variant | 11/18 | ENST00000646891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRAF | ENST00000644969.2 | c.1525G>C | p.Gly509Arg | missense_variant | 12/20 | NM_001374258.1 | |||
BRAF | ENST00000646891.2 | c.1405G>C | p.Gly469Arg | missense_variant | 11/18 | NM_004333.6 | P4 | ||
ENST00000700122.1 | n.502+6735C>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1AN: 1461752Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727182
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Prostate adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Multiple myeloma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Squamous cell carcinoma of the skin Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Squamous cell lung carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Cardio-facio-cutaneous syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 17, 2021 | Variant summary: BRAF c.1405G>C (p.Gly469Arg) results in a non-conservative amino acid change located in the Serine-threonine/tyrosine-protein kinase, catalytic 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 251420 control chromosomes. c.1405G>C has been widely reported in the literature as a somatic variant in a variety of cancers such as melanoma and in at-least one case of fetal autopsy findings of Cardiofaciocutaneous Syndrome (example, Terry_2014). In the fetal case, both parents denied having personal or family histories of genetic disorders, malformations, or other significant abnormalities. Therefore, although a de-novo etiology is likely, it was not unequivocally established by parental analysis as reported in this study. Furthermore, pathogenic/likely pathogenic variants in HRAS, KRAS, MAP2K1, MAP2K2, PTPN11, RAF1, SOS1, and exon 2 of SHOC2 were reportedly not identified. At least one publication reports experimental evidence evaluating an impact on protein function (Damm_2014). The most pronounced variant effect results in constitutive ERK phosphorylation and Egr2 transcription along with a decrease in the proprtion of B cells in BRAF-G469R mice, as compared with empty murine stem cell virus vector or BRAF-wild type mice. No clinical diagnostic laboratories have submitted germline clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Lung adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
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 | Dec 17, 2012 | The G469R missense mutation has not been reported as a germline mutation to our knowlege; however, a different mutation at this residue (G469E) has been described in patients with Cardio-Facio-Cutaneous (CFC) Syndrome (Niihori et al., 2006). The G469R mutation identified in the fetus has been reported previously as a somatic mutation in association with haematopoietic and lymphoid cancer (Catalogue of Somatic Mutations in Cancer). The G469R missense change is a non-conservative substitution with a neutral, non-polar Gly residue being replaced by a positively-charged Arg residue. The NHLBI ESP Exome Variant Server reports that G469R was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The variant is found in NOONAN panel(s). - |
Transitional cell carcinoma of the bladder Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Non-Hodgkin lymphoma Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 17, 2003 | - - |
Malignant melanoma of skin Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of the large intestine Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at