KRAS c.35G>A, p.Gly12Asp
NM_033360.2:c.35G>A
COSMIC ID: COSM521
Pathogenic
This KRAS Gly12Asp variant meets three Moderate criteria (PS3, PM1, PM5) and two Supporting criteria (PP3, PP5) under VCEP-modified ACMG rules, resulting in a classification of Likely Pathogenic.
ACMG/AMP Criteria Applied
PS3
PM1
PM5
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_033360.2:c.35G>A
Protein Change
G12D
Location
Exon 2
(Exon 2 of 6)
5'Exon Structure (6 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 12: G12F, G12A, G12V, G12C, G12S, G12R, G12C
Alternate Identifiers
COSM521
Variant interpretation based on transcript NM_033360.2
Genome Browser
Loading genome browser...
HGVS InputNM_033360:c.35G>A
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Global Frequency
0.000401%
Extremely Rare
Highest in Population
European (non-Finnish)
0.000888%
Very Rare
Global: 0.000401%
European (non-Finnish): 0.000888%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 249328Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000401%, 1/249328 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.000888%, 1/112572 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
12 publications
Likely Pathogenic
Based on 18 submitter reviews in ClinVar
Submitter Breakdown
17 Path
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (12)
Somatic KRAS variants have been identified in up to 15% of cases of ovarian carcinoma, and Gly12Asp accounts for 40% of the identified KRAS variants (COSMIC 2010; Auner 2009).
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (17 clinical laboratories) and as Likely pathogenic (1 clinical laboratories).
COSMIC ID
COSM521
Recurrence
16586 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
COSMIC Database Preview
Accessing full COSMIC database details requires institutional login or subscription. External links may prompt for authentication.
Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
21750
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (21750 mutations).
PM1 criterion applied.
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 12: G12F, G12A, G12V, G12C, G12S, G12R, G12C
PM5 criterion applied.
Functional Summary
Gain-of-Function
The KRAS G12D variant has been functionally characterized as a gain-of-function mutation. It is known to be oncogenic, leading to increased downstream pathway activation, enhanced colony formation, and in vivo tumor development across multiple cancer types. Additionally, this variant confers resistance to BRAF inhibition but shows sensitivity to MEK inhibitors like cobimetinib. Preclinical studies have also demonstrated sensitivity to ASP3082 treatment, as evidenced by reduced tumor volume in xenograft mouse models.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.875
0.875
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: 5.13polyphen_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 PVS1 rule 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 (Gly12Asp), not predicted to cause loss of function. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the PS1 rule is: 'Strong – Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows no alternative nucleotide change producing Gly12Asp beyond c.35G>A. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PS2 rule is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to VCEP guidelines, the PS3 rule is: 'Moderate Strength: Moderate – Two or more different approved assays.' The evidence for this variant shows multiple in vitro and in vivo functional studies demonstrating gain-of-function, increased downstream pathway activation, enhanced colony formation, in vivo tumor development, and treatment responses in xenograft models. Therefore, this criterion is applied at Moderate strength because the variant has been characterized by multiple different approved assays.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the PS4 rule is: 'Strong – ≥5 points; Moderate – ≥3 points; Supporting – ≥1 point from case–control data or case series.' No case–control or case series data are available in the germline context. Therefore, this criterion is not applied.
PM1
PM1 (Moderate)
According to VCEP guidelines, the PM1 rule is: 'Moderate Strength: Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]).' Gly12 lies within the P-loop (AA 10-17). Therefore, this criterion is applied at Moderate strength.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the PM2 rule is: 'Supporting Strength: The variant must be absent from controls (gnomAD).' The evidence for this variant shows it is present in gnomAD at MAF=0.000401%. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM3 rule is: 'For recessive disorders, detected in trans with a pathogenic variant.' This is not applicable to KRAS gain-of-function variants. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM4 rule is: 'Protein length changes due to in-frame deletions/insertions or stop-loss.' This variant is a missense change. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines, the PM5 rule is: 'Moderate Strength: 1 likely pathogenic residue change at the same codon.' Other missense variants at codon 12 (e.g., G12C, G12V, G12S) have been established as pathogenic. Therefore, this criterion is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM6 rule is: 'Assumed de novo, but without confirmation of paternity and maternity.' No de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP1 rule is: 'Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.' No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP2 rule is: 'Missense variant in a gene with a low rate of benign missense variation and where missense is a common mechanism of disease.' Although KRAS missense variants are disease-causing, this criterion was not applied in the original pipeline and no additional gene-specific data support its use. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the PP3 rule is: 'Supporting Strength: For missense variants: REVEL ≥0.7.' The evidence for this variant shows a REVEL score of 0.88. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP4 rule is: 'Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.' No germline phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the PP5 rule is: 'Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory for independent evaluation.' The evidence for this variant shows ClinVar submissions reporting it as Pathogenic (17 labs) and Likely Pathogenic (1 lab). Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BA1 rule is: 'Allele frequency is >5% in population databases.' The evidence for this variant shows frequency <<5%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the BS1 rule is: 'Strong Strength: GnomAD filtering allele frequency ≥0.025%.' The evidence for this variant shows MAF=0.000401%, which is below the threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BS2 rule is: 'Observed in a healthy adult individual for a recessive (homozygous) or dominant (heterozygous) disorder.' No such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BS3 rule is: 'Well-established in vitro or in vivo functional studies show no damaging effect.' Functional studies for this variant show damaging gain-of-function. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BS4 rule is: 'Lack of 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 standard ACMG guidelines, the BP1 rule is: 'Missense variant in a gene for which primarily truncating variants are known to cause disease.' KRAS disease mechanism is gain-of-function by missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP2 rule is: 'Observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance.' No data support this. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP3 rule is: 'In-frame deletions/insertions in a repetitive region without a known function.' This is a missense variant. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP4 rule is: 'Multiple lines of computational evidence suggest no impact on gene/gene product.' Computational evidence here supports deleterious effect. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP5 rule is: 'Variant found in a case with an alternate molecular basis for disease.' No such alternate etiology is documented. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP6 rule is: 'Reputable source reports variant as benign, but evidence not available.' No reputable benign reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP7 rule is: 'Synonymous variant with no predicted splice impact and the nucleotide not highly conserved.' This variant is missense. Therefore, this criterion is not applied.