KRAS c.437C>T, p.Ala146Val
NM_033360.4:c.437C>T
COSMIC ID: COSM19900
Pathogenic
KRAS A146V (c.437C>T) is classified as Pathogenic based on VCEP-guided application of PS3 (Moderate), PM1 (Moderate), PM5 (Moderate), PM2, PP2, PP3, and PP5 (Supporting), with robust functional and computational evidence supporting a damaging gain-of-function effect.
ACMG/AMP Criteria Applied
PS3
PM1
PM2
PM5
PP2
PP3
PP5
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.437C>T
Protein Change
A146V
Location
Exon 4
(Exon 4 of 6)
5'Exon Structure (6 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 146: A146P, A146T, A146S
Alternate Identifiers
COSM19900
Variant interpretation based on transcript NM_033360.2
Genome Browser
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HGVS InputNM_033360:c.437C>T
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
2 publications
Likely Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
1 Path
1 LP
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRAS protein function. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 146 of the KRAS protein (p.Ala146Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with mosaic RASopathy (PMID: 26970110, 30891959). ClinVar contains an entry for this variant (Variation ID: 375962). Experimental studies have shown that this missense change affects KRAS function (PMID: 30448735). This variant disrupts the p.Ala146 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and as Likely pathogenic (1 clinical laboratories) and as Pathogenic (1 clinical laboratories).
COSMIC ID
COSM19900
Recurrence
99 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
258
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (258 mutations).
PM1 criterion applied.
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 146: A146P, A146T, A146S
PM5 criterion applied.
Functional Summary
The KRAS A146V variant has been functionally characterized as an activating mutation. Experimental evidence demonstrates increased protein activation and colony formation in fibroblast and embryonic kidney cells, as well as enhanced MAPK signaling in Ba/F3 cells compared to the wildtype. Additionally, this variant confers resistance to BRAF inhibition but remains sensitive to MEK inhibition, as evidenced by in vitro studies and clinical response in a patient with hairy cell leukemia. These findings support a damaging effect of the KRAS A146V variant.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.89
0.89
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: 6.18
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: 'Very Strong Strength: null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multiexon deletion).' The evidence for this variant shows: A146V is a missense change, 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 Strength: same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows: no prior report of the A146V amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'Very Strong Strength: de novo (both maternity and paternity confirmed).' The evidence for this variant shows: no parental or de novo data available. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Moderate Strength: two or more different approved assays.' The evidence for this variant shows: multiple functional assays (fibroblast colony formation, embryonic kidney cell activation, Ba/F3 MAPK signaling) demonstrating a damaging effect. Therefore, this criterion is applied at Moderate strength because two or more different approved assays support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Strong Strength: ≥5 points.' The evidence for this variant shows: no case/control data or point counts available. 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 AA10-17, SW1 AA25-40, SW2 AA57-64, SAK AA145-156).' The evidence for this variant shows: A146V lies within the SAK domain (AA145-156). Therefore, this criterion is applied at Moderate strength because the variant resides in a critical functional domain.
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: not found in gnomAD. 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: 'Moderate Strength: detected in trans with a pathogenic variant for a recessive disorder.' The evidence for this variant shows: no in trans or recessive data. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Moderate Strength: protein length changes (in-frame indels or stop-loss variants).' The evidence for this variant shows: A146V is a missense change without alteration of protein length. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines, the rule for PM5 is: 'Moderate Strength: one (likely) pathogenic residue change at the same codon.' The evidence for this variant shows: other pathogenic substitutions at codon 146 (e.g., A146T) have been reported. Therefore, this criterion is applied at Moderate strength because a known pathogenic residue change occurs at the same codon.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Moderate Strength: assumed de novo without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Supporting Strength: cosegregation with disease in multiple affected family members.' The evidence for this variant shows: no familial segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Supporting)
According to standard ACMG guidelines, the rule for PP2 is: 'Supporting Strength: missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease.' The evidence for this variant shows: KRAS disease mechanism is gain-of-function via missense changes and benign missense is rare. Therefore, this criterion is applied at Supporting strength because missense is the established disease mechanism in KRAS.
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 of 0.89. Therefore, this criterion is applied at Supporting strength because computational evidence supports a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Supporting Strength: patient phenotype or family history is highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no clinical phenotype data provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: 'Supporting Strength: reputable source recently reports variant as pathogenic, but evidence is unavailable for independent evaluation.' The evidence for this variant shows: ClinVar includes at least one pathogenic entry. Therefore, this criterion is applied at Supporting strength because a reputable database reports pathogenic classification.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Stand Alone Strength: allele frequency ≥0.05% in gnomAD.' The evidence for this variant shows: allele frequency 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Strong Strength: allele frequency greater than expected for disorder (≥0.025%).' The evidence for this variant shows: allele frequency 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Strong Strength: observed in healthy adult controls for a fully penetrant dominant disorder.' The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong Strength: well-established functional studies show no damaging effect.' The evidence for this variant shows: 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: 'Strong Strength: non-segregation in affected family members.' 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 variant in a gene where disease mechanism is gain-of-function.' The evidence for this variant shows: A146V is a missense variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Supporting Strength: 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 such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'Supporting Strength: in-frame indels in repetitive regions without known function.' The evidence for this variant shows: A146V is a missense change. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: 'Supporting Strength: REVEL ≤0.3.' The evidence for this variant shows: REVEL score 0.89. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Supporting Strength: variant found in case with an alternate molecular basis for disease.' The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Supporting Strength: reputable source reports variant as benign, but evidence is unavailable for independent evaluation.' The evidence for this variant shows: no benign reports in ClinVar. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Supporting Strength: synonymous variant with no predicted splicing impact and low conservation.' The evidence for this variant shows: A146V is a missense change. Therefore, this criterion is not applied.