KRAS c.176C>G, p.Ala59Gly
NM_033360.2:c.176C>G
COSMIC ID: COSM1135365
Pathogenic
KRAS A59G meets three moderate criteria (PS3, PM1, PM5) and two supporting criteria (PM2, PP3) under VCEP guidelines, consistent with a Likely Pathogenic classification.
ACMG/AMP Criteria Applied
PS3
PM1
PM2
PM5
PP3
Genetic Information
Gene & Transcript Details
Gene
KRAS
Transcript
NM_033360.2
Total Exons
6
Strand
Reverse (−)
Reference Sequence
NC_000012.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_033360.4 | Alternative | 6 exons | Reverse |
| NM_033360.3 | Alternative | 6 exons | Reverse |
Variant Details
HGVS Notation
NM_033360.2:c.176C>G
Protein Change
A59G
Location
Exon 3
(Exon 3 of 6)
5'Exon Structure (6 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 59: A59L, A59S, A59T
Alternate Identifiers
COSM1135365
Variant interpretation based on transcript NM_033360.2
Genome Browser
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HGVS InputNM_033360:c.176C>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
COSMIC ID
COSM1135365
Recurrence
25 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
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Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
48
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (48 mutations).
PM1 criterion applied.
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 59: A59L, A59S, A59T
PM5 criterion applied.
Functional Summary
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.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.704
0.704
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
metasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.42polyphen_prediction: benign
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
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
PS1 (Not Applied) Strength Modified
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
PS2 (Not Applied) Strength Modified
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
PS3 (Moderate) Strength Modified
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
PS4 (Not Applied) Strength Modified
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
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
PM2 (Supporting) Strength Modified
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
PM3 (Not Applied) Strength Modified
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
PM4 (Not Applied) Strength Modified
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
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
PM6 (Not Applied) Strength Modified
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
PP1 (Not Applied) Strength Modified
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
PP2 (Not Applied) Strength Modified
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
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
PP4 (Not Applied) Strength Modified
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
PP5 (Not Applied) Strength Modified
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
BA1 (Not Applied) Strength Modified
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
BS1 (Not Applied) Strength Modified
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
BS2 (Not Applied) Strength Modified
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
BS3 (Not Applied) Strength Modified
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
BS4 (Not Applied) Strength Modified
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
BP1 (Not Applied) Strength Modified
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
BP2 (Not Applied) Strength Modified
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
BP3 (Not Applied) Strength Modified
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
BP4 (Not Applied) Strength Modified
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
BP5 (Not Applied) Strength Modified
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
BP6 (Not Applied) Strength Modified
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
BP7 (Not Applied) Strength Modified
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.