KRAS c.182_183delinsTC, p.Gln61Leu
NM_033360.4:c.182_183delinsTC
COSMIC ID: COSM1166780, COSM6957661
Likely Pathogenic
Likely Pathogenic based on PS1 (Strong) for established Q61L pathogenic change, PM1 (Moderate) for localization in SW2 domain, PM2 (Supporting) for absence from controls, and PS3 (Supporting) for functional evidence of oncogenic activation.
ACMG/AMP Criteria Applied
PS1
PS3
PM1
PM2
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_033360.4:c.182_183delinsTC
Protein Change
Q61L
Location
Exon 3
(Exon 3 of 6)
5'Exon Structure (6 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 61 in gene KRAS
Alternate Identifiers
COSM1166780, COSM6957661
Variant interpretation based on transcript NM_033360.2
Genome Browser
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HGVS InputNM_033360:c.182_183delinsTC
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
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 61 in gene KRAS
Functional Summary
The KRAS Q61L 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, with increased pathway activation compared to the wildtype in murine cell models.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
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 variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multiexon deletion) in a gene where loss of function is a known mechanism of disease.” The evidence for this variant shows it is a missense change (Q61L), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Strong)
According to VCEP guidelines, PS1 strong strength: “Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.” The evidence for this variant shows Q61L is a well‐established pathogenic amino acid change in KRAS. Therefore, this criterion is applied at Strong strength because the amino acid change matches a known pathogenic variant.
PS2
PS2 (Not Applied) Strength Modified
According to Standard ACMG guidelines, the rule for PS2 is: “De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.” No inheritance or parental testing data are available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Supporting) Strength Modified
According to VCEP guidelines, PS3 supporting strength: “One approved assay showing a damaging effect.” The evidence for this variant shows functional characterization in murine cell models demonstrating oncogenic activation (increased pathway activation). Therefore, this criterion is applied at Supporting strength because one disease‐specific functional assay supports a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 strong strength: “≥5 points from case‐control or case series data.” No case‐control or case‐series data or point counts are available. Therefore, this criterion is not applied.
PM1
PM1 (Moderate)
According to VCEP guidelines, PM1 moderate strength: “Variant is within a critical and well‐established functional domain (SW2 [AA 57–64]).” The evidence for this variant shows Q61 resides within the SW2 domain (AA 57–64) of KRAS. Therefore, this criterion is applied at Moderate strength because the variant lies in a mutational hotspot domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 supporting strength: “Absent from controls (gnomAD).” The evidence for this variant shows it is not found in gnomAD or other population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
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.” This variant is associated with a dominant gain‐of‐function mechanism and there is no evidence of trans configuration in a recessive context. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to Standard ACMG guidelines, the rule for PM4 is: “Protein length changes as a result of in‐frame deletions/insertions in a non‐repeat region.” This variant is a missense substitution (delins results in Q61L), not a length‐altering in‐frame indel. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 strong strength requires: “≥2 different pathogenic residue changes at the same codon observed in ≥5 probands.” While other Q61 substitutions (e.g., Q61R, Q61K) are pathogenic, specific proband counts are not available. Therefore, this criterion is not applied due to insufficient proband data.
PM6
PM6 (Not Applied) Strength Modified
According to Standard ACMG guidelines, the rule for PM6 is: “Assumed de novo, but without confirmation of paternity and maternity.” No de novo data are provided. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to Standard ACMG guidelines, the rule for PP1 is: “Co‐segregation with disease in multiple affected family members.” 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 gene with low rate of benign missense variation (<0.5%).” Specific data on benign missense rate in KRAS are not provided. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 supporting strength requires: “REVEL ≥0.7 for missense variants.” No REVEL score is available; computational predictions are mixed. Therefore, this criterion is not applied.
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.” No clinical phenotype or family history is provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to Standard ACMG guidelines, the rule for PP5 is: “Reputable source recently reports variant as pathogenic, but evidence not available.” The variant is not present in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 stand alone: “MAF ≥0.05% in gnomAD.” The variant is absent from gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 strong strength: “MAF ≥0.025% in gnomAD.” The variant is absent from gnomAD. 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 fully penetrant dominant disorder.” No observations in healthy individuals are reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to Standard ACMG guidelines, the rule for BS3 is: “Well‐established functional studies show no damaging effect.” Functional studies demonstrate a damaging, activating effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to Standard ACMG guidelines, the rule for BS4 is: “Non‐segregation in affected members of a family.” No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, BP1 supporting strength: “Truncating variants in a gain‐of‐function gene.” This variant 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.” No such data are available. 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 a repetitive region without a known function.” This variant is a missense change, not an in‐frame indel in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 supporting strength: “REVEL ≤0.3 for missense variants.” No REVEL score is available; computational predictions are mixed. 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.” No alternate molecular basis is reported. 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.” No such report exists. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to Standard ACMG guidelines, the rule for BP7 is: “Synonymous variant with no predicted splicing impact and not highly conserved.” This variant is missense, not synonymous. Therefore, this criterion is not applied.