Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_033360.2 | Alternative | 5436 nt | 182–751 |
| NM_033360.4 | Alternative | 5430 nt | 191–760 |
| NM_033360.3 | Alternative | 5889 nt | 193–762 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The KRAS A59G variant has been functionally characterized as oncogenic. It is located in the catalytic G-domain of the KRAS protein and has been shown to be activating. Experimental studies in human embryonic kidney cell lines have demonstrated increased protein activation, downstream pathway activation, and enhanced tumor growth in vivo compared to the wildtype.
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -3 bp |
| Donor Loss (DL) | 0.21 | -2 bp |
| Acceptor Gain (AG) | 0.01 | 0 bp |
| Donor Gain (DG) | 0.0 | -114 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variants (nonsense, frameshift, canonical splice site, initiation codon loss, or single/multi-exon deletion) in a gene where loss of function is a known mechanism of disease are considered very strong evidence of pathogenicity.' The evidence for this variant shows: NM_033360.2:c.176C>G is a missense change (A59G), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: 'Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in HRAS, KRAS, MRAS, NRAS, RIT1, and RRAS2.' The evidence for this variant shows: A59G is a novel amino acid change not previously established as pathogenic. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: 'Very Strong 4 Points; Strong 2 Points; Moderate 1 Point for de novo occurrences.' The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PS3 (Moderate)
According to VCEP guidelines, the rule for PS3 is: 'Moderate Strength: Moderate Two or more different approved assays. Modification Type: Disease-specific,Gene-specific,Strength.' The evidence for this variant shows: KRAS A59G has been characterized by in vitro assays (increased GTP binding and downstream signaling) and in vivo tumor growth studies, representing at least two different approved assays. Therefore, this criterion is applied at Moderate strength.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'Strong ≥5 points; Moderate ≥3 points; Supporting ≥1 point based on case–control or case series data.' The evidence for this variant shows: no case or control frequency data in affected individuals are reported. Therefore, this criterion is not applied.
PM1 (Moderate)
According to VCEP guidelines, the rule for PM1 is: 'Moderate Strength: Applicable only to critical and well-established functional domains (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]).' The evidence for this variant shows: A59 is within the SW2 domain (AA 57-64) of KRAS, a critical functional region. Therefore, this criterion is applied at Moderate strength.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: 'Supporting Strength: The variant must be absent from controls (gnomAD).' The evidence for this variant shows: c.176C>G is not present in gnomAD or other population databases. Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant for a recessive disorder.' The evidence for this variant shows: no data on trans configuration in a recessive context. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: 'Moderate Strength: protein length changes due to in-frame indels or stop loss in non-repetitive regions.' The evidence for this variant shows: A59G is a missense substitution, not a protein length change. Therefore, this criterion is not applied.
PM5 (Moderate)
According to VCEP guidelines, the rule for PM5 is: 'Moderate Strength: 1 [likely] pathogenic residue change at the same codon.' The evidence for this variant shows: a different missense change at codon 59 (e.g., A59T) has been previously reported as pathogenic. Therefore, this criterion is applied at Moderate strength.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo without confirmation of paternity/maternity.' The evidence for this variant shows: no de novo assumption data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: 'Supporting Strength: ≥3 informative meioses; Moderate ≥5 meioses; Strong ≥7 meioses for segregation evidence.' The evidence for this variant shows: no family segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with low rate of benign missense variation and for which missense is a common mechanism of disease.' The evidence for this variant shows: insufficient data on benign missense variation rate; no clear justification. Therefore, this criterion is not applied.
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: 'Supporting Strength: For missense variants, REVEL ≥0.7.' The evidence for this variant shows: REVEL score is 0.70. Therefore, this criterion is applied at Supporting strength.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no clinical phenotype or family history data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic without available evidence.' The evidence for this variant shows: no such reports exist. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone Strength: gnomAD filtering allele frequency ≥0.05%.' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'Strong Strength: gnomAD filtering allele frequency ≥0.025%.' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy adult individuals for a dominant condition.' The evidence for this variant shows: no observations in healthy adults. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: 'Strong evidence of no functional impact from well-established assays.' The evidence for this variant shows: functional assays demonstrate damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected members of a family.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines, the rule for BP1 is: 'Supporting Strength: truncating variants in RASopathy genes are used as benign evidence.' The evidence for this variant shows: A59G is missense, not truncating. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.' The evidence for this variant shows: no data on trans or cis observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in repetitive regions without known function.' The evidence for this variant shows: A59G is a missense change, not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: 'Supporting Strength: For missense variants, REVEL ≤0.3.' The evidence for this variant shows: REVEL is 0.70. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no alternate molecular basis identified. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign without available evidence.' The evidence for this variant shows: no such benign reports exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant without predicted splice impact and nucleotide not highly conserved.' The evidence for this variant shows: A59G is a missense change, not synonymous. Therefore, this criterion is not applied.