NM_001374258.1:c.1901A>G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP2PP3_StrongPP5
The NM_001374258.1(BRAF):c.1901A>G(p.Asp634Gly) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D634V) has been classified as Pathogenic.
Frequency
Consequence
NM_001374258.1 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRAF | ENST00000644969.2 | c.1901A>G | p.Asp634Gly | missense_variant | Exon 16 of 20 | NM_001374258.1 | ENSP00000496776.1 | |||
BRAF | ENST00000646891.2 | c.1781A>G | p.Asp594Gly | missense_variant | Exon 15 of 18 | NM_004333.6 | ENSP00000493543.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Lung adenocarcinoma Pathogenic:1
- -
Non-small cell lung carcinoma Pathogenic:1
This variant has been reported as a somatic change in large intestine, skin, end ometrium, stomach, and ovary (COSMIC, Fransen 2004) and has been observed in up to 11% of BRAF mutant positive lung adenocarcinoma (Paik 2011). -
Non-Hodgkin lymphoma Pathogenic:1
- -
RASopathy Uncertain:1
This sequence change replaces aspartic acid with glycine at codon 594 of the BRAF protein (p.Asp594Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with BRAF-related conditions. ClinVar contains an entry for this variant (Variation ID: 13972). 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. Experimental studies have shown that this variant affects BRAF function (PMID: 23352452, 29595366). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Neoplasm Other:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at