KRAS c.35G>A, p.Gly12Asp
NM_033360.2:c.35G>A
COSMIC ID: COSM521
Pathogenic
Pathogenic classification is supported by Moderate evidence from functional assays (PS3), location in the P-loop domain (PM1), analogous pathogenic changes at the same codon (PM5), plus Supporting computational evidence (PP3) and reputable source reports (PP5).
ACMG/AMP Criteria Applied
PS3
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
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HGVS InputNM_033360:c.35G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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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
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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 in multiple cancer types. This variant also confers resistance to BRAF inhibition but shows sensitivity to MEK inhibitors like cobimetinib. Preclinical studies have demonstrated that KRAS G12D is sensitive to treatment with ASP3082, 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 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 (G12D), not a null variant. Therefore, this criterion is not applied because the variant does not meet the null variant requirement.
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: the nucleotide change is the same as the established G12D change, not a different nucleotide producing the same amino acid. Therefore, this criterion is not applied because the requirement of a different nucleotide change is not met.
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." The evidence for this variant shows: no de novo inheritance data are available. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Moderate) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Moderate Strength: Two or more different approved assays. Modification Type: Disease-specific,Gene-specific,Strength." The evidence for this variant shows: multiple functional studies including in vitro gain-of-function assays, colony formation assays, in vivo tumor development models, and xenograft drug response assays. Therefore, this criterion is applied at Moderate strength because multiple distinct functional assays demonstrate a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong Strength: ≥5 points; Moderate Strength: ≥3 points; Supporting Strength: ≥1 points. Modification Type: Disease-specific." The evidence for this variant shows: no formal case-control or proband point counts have been provided. Therefore, this criterion is not applied due to absence of case count data.
PM1
PM1 (Moderate)
According to VCEP guidelines, the rule for PM1 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]). Not applicable to specific amino acid residues (see PM5). Modification Type: Gene-specific." The evidence for this variant shows: it affects amino acid 12, which lies within the P-loop (AA 10-17). Therefore, this criterion is applied at Moderate strength because the variant is in a critical functional domain.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: The variant must be absent from controls (gnomAD). Modification Type: Strength." The evidence for this variant shows: it is present in gnomAD at MAF = 0.000401%. Therefore, this criterion is not applied because the variant is not absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: no data on trans observations 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: No known repetitive areas in gene. Use as described. Modification Type: General recommendation." The evidence for this variant shows: it is a missense substitution, not an in-frame insertion/deletion. 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. Modification Type: Analogous Gene,Disease-specific." The evidence for this variant shows: other missense changes at codon 12 (e.g., G12V, G12C, G12A) have been established as pathogenic. Therefore, this criterion is applied at Moderate strength because at least one other pathogenic residue change is known at the same codon.
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." The evidence for this variant shows: no de novo data are available. 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; Strong: ≥7." The evidence for this variant shows: no segregation data 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 where missense is a common mechanism of disease." The evidence for this variant shows: KRAS has many pathogenic and benign missense variants; no specific constraint information provided. 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. Modification Type: Disease-specific." The evidence for this variant shows: REVEL score = 0.88, exceeding the threshold. Therefore, this criterion is applied at Supporting strength because multiple computational tools predict a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is specific for a disease with a single genetic etiology." The evidence for this variant shows: no germline phenotype or clinical presentation data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: ClinVar entries include 17 clinical laboratories reporting Pathogenic. Therefore, this criterion is applied at Supporting strength because a reputable database lists it as pathogenic without available primary evidence.
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: MAF = 0.000401%, well below the threshold. 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: MAF = 0.000401%, below the threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a recessive (homozygous) or dominant (heterozygous) condition without any clinical evidence of disease." The evidence for this variant shows: no data from healthy adult carriers. 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 on protein function or splicing." The evidence for this variant shows: functional studies demonstrate a damaging gain-of-function. 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 available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP1 is: "Supporting Strength: any truncating variant in genes without established loss-of-function correlation to disease." The evidence for this variant shows: it is a 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 dominant disorders, or in cis with a pathogenic variant for any disorder." The evidence for this variant shows: no such observations reported. 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 a known function." The evidence for this variant shows: it is a missense variant. 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 = 0.88. 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 such alternate findings 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 as benign without available evidence." The evidence for this variant shows: no reputable source lists it as benign. 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 splice impact and not highly conserved." The evidence for this variant shows: it is a missense variant. Therefore, this criterion is not applied.