KRAS c.175G>A, p.Ala59Thr
NM_033360.2:c.175G>A
COSMIC ID: COSM546
Pathogenic
KRAS A59T is a gain-of-function missense variant in the SW2 domain, absent from population databases, with strong functional and computational evidence; applying VCEP-specified strengths yields two Moderate (PS3, PM1, PM5) and two Supporting (PM2, PP3) criteria, 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.175G>A
Protein Change
A59T
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
Alternate Identifiers
COSM546
Variant interpretation based on transcript NM_033360.2
Genome Browser
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HGVS InputNM_033360:c.175G>A
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
Not Classified
Publications (0)
No publication details.
Clinical Statement
Present in ClinVar, however no clinical evidence available for this variant.
COSMIC ID
COSM546
Recurrence
47 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
COSMIC Database Preview
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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
PM5 criterion applied.
Functional Summary
Gain-of-Function
The KRAS A59T variant has been functionally characterized as a gain-of-function mutation. Experimental evidence demonstrates that this variant is oncogenic, leading to increased cell proliferation and migration in NIH3T3 cells, as well as enhanced MAPK signaling in Ba/F3 cells compared to the wildtype. These findings support a damaging effect of the KRAS A59T mutation.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.869
0.869
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
Yes
Additional Predictors
Pathogenic:
metasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.50
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, PVS1 addresses null variants in genes where loss-of-function is a known mechanism. KRAS-associated disease mechanism is gain-of-function and this variant is a missense change. The evidence shows a missense alteration (A59T). Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 (Strong) requires the same amino acid change as a previously established pathogenic variant. The evidence shows no identical A59T nucleotide change previously reported as pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 (Strong) applies to de novo occurrences with confirmed parentage. No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to VCEP guidelines, PS3 (Moderate) is met by two or more different approved functional assays. The evidence shows oncogenic gain-of-function demonstrated by increased cell proliferation in NIH3T3 cells and enhanced MAPK signaling in Ba/F3 cells. Therefore, this criterion is applied at Moderate strength.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 (Strong) requires ≥5 proband points. No case-level data or point counts are available. Therefore, this criterion is not applied.
PM1
PM1 (Moderate)
According to VCEP guidelines, PM1 (Moderate) applies to variants in the SW2 region (AA 57–64). A59T lies within SW2. Therefore, this criterion is applied at Moderate strength.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 (Supporting) applies when the variant is absent from gnomAD. The evidence shows A59T is not present in gnomAD. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 (Moderate) applies to recessive disorders with detected trans variants. KRAS A59T is associated with a dominant oncogenic mechanism, and no trans data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 (Moderate) applies to in-frame insertions/deletions or stop-loss variants. A59T is a missense change. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines, PM5 (Moderate) applies when one other pathogenic residue change at the same codon is reported. A59G has been established as pathogenic. Therefore, this criterion is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 (Supporting) applies to assumed de novo variants without confirmation. No de novo evidence is available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 (Supporting) requires segregation data. No family segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 (Supporting) applies when a gene has a low rate of benign missense variation. No specific constraint metrics or gene-level data were provided. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, PP3 (Supporting) applies for missense variants with REVEL ≥0.7. The evidence shows a REVEL score of 0.87. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 (Supporting) requires a highly specific phenotype. No phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 (Supporting) applies when reputable sources report the variant as pathogenic without evidence. ClinVar has no assertion for this variant. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BA1 (Stand Alone) requires population allele frequency ≥5%. The variant is absent from controls. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS1 (Strong) requires allele frequency ≥2.5%. The variant is absent from controls. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS2 (Strong/Supporting) applies when observed in multiple healthy individuals. No such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS3 (Strong) applies when well-established functional studies show no damaging effect. Functional studies for A59T demonstrate gain-of-function. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 (Strong) requires non-segregation in affected members. No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 (Supporting) applies to truncating variants in genes not associated with loss-of-function. A59T is missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 (Supporting) applies to observation in trans with a pathogenic variant in dominant disorders. No such data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 (Supporting) applies to in-frame indels in repetitive regions. A59T is a missense change. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 (Supporting) applies for missense variants with REVEL ≤0.3. The REVEL score is 0.87, well above threshold. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 (Supporting) applies when a variant is found in a case with an alternate molecular cause. No alternate cause data are available. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 (Supporting) applies when reputable sources report as benign without evidence. No such reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 (Supporting) applies to synonymous changes with no predicted splice impact. A59T is missense. Therefore, this criterion is not applied.