rs121913535
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_004985.5(KRAS):c.37G>T(p.Gly13Cys) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G13A) has been classified as Pathogenic.
Frequency
Consequence
NM_004985.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KRAS | NM_033360.4 | c.37G>T | p.Gly13Cys | missense_variant | 2/6 | ENST00000256078.10 | |
KRAS | NM_004985.5 | c.37G>T | p.Gly13Cys | missense_variant | 2/5 | ENST00000311936.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRAS | ENST00000256078.10 | c.37G>T | p.Gly13Cys | missense_variant | 2/6 | 1 | NM_033360.4 | A1 | |
KRAS | ENST00000311936.8 | c.37G>T | p.Gly13Cys | missense_variant | 2/5 | 1 | NM_004985.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Autoimmune lymphoproliferative syndrome type 4 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID:. 29493581. Predicted Consequence/Location:). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000045123 / PMID: 27577878). Different missense changes at the same codon (p.Gly13Ala, p.Gly13Arg, p.Gly13Asp, p.Gly13Ser, p.Gly13Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012580, VCV000012593, VCV000045124, VCV000375967, VCV000375968, VCV001691382 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 10, 2011 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine | Jan 03, 2023 | - - |
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 21, 2022 | Published functional studies demonstrate that this variant causes increased RAS activation (Niemela et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 19661383, 22306671, 17517660, 25705018, 25691160, 21063026, 34056834, 22571758, 29493581, 21079152, 17875937, 27577878, 35116442) - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jan 22, 2019 | - - |
Non-small cell lung carcinoma Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 17, 2012 | - - |
KRAS-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has been previously reported as a somatic/ mosaic change in patients with RAS-associated autoimmune leukoproliferative disorder (PMID: 27577878, 21079152). Cells transfected with a plasmid-encoding mutant G13C showed an increased amount of active RAS versus wild-type KRAS suggesting a gain-of-function effect (PMID: 21079152). The c.37G>T (p.Gly13Cys) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.37G>T (p.Gly13Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.37G>T (p.Gly13Cys) variant is classified as Pathogenic. - |
Neoplasm of the large intestine Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at