KRASc.34G>CLikely pathogenic

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Variant interpretation report

KRAS c.34G>C, p.(Gly12Arg)

NM_033360.2:c.34G>C NP_203524.1:p.(Gly12Arg) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About KRAS

No gene-level summary was recorded for this case.

Key facts

Evidence used: 2 moderate (pathogenic) · 2 supporting (pathogenic)
Expert rules: ClinGen KRAS VCEP v2.3.0

Evidence considered

View criteria

Applied evidence criteria

PM1 (moderate): This variant affects codon 12 within the KRAS P-loop functional domain, which lies in the VCEP-defined PM1 region spanning amino acids 10 to 17, supporting PM1 at a moderate strength.
PM2 (supporting): This variant is absent from population controls in gnomAD, with 0/249272 alleles in gnomAD v2.1 and no observation in gnomAD v4.1, meeting the KRAS VCEP PM2_Supporting rule.
PM5 (moderate): This missense variant affects codon 12, where other pathogenic missense substitutions have already been established within the RASopathy VCEP framework, so PM5 is met at a moderate strength.
PP3 (supporting): Available computational evidence supports a damaging missense effect because the REVEL score is 0.821, which is above the KRAS VCEP PP3 threshold of 0.7; SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is ClinGen KRAS VCEP v2.3.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 4 Benign evidence criteria: 0

Pathogenic criteria applied · 4

PM1Moderate

PM1 · moderate

This variant affects codon 12 within the KRAS P-loop functional domain, which lies in the VCEP-defined PM1 region spanning amino acids 10 to 17, supporting PM1 at a moderate strength.

PM2Supporting

PM2 · supporting

This variant is absent from population controls in gnomAD, with 0/249272 alleles in gnomAD v2.1 and no observation in gnomAD v4.1, meeting the KRAS VCEP PM2_Supporting rule.

PM5Moderate

PM5 · moderate

This missense variant affects codon 12, where other pathogenic missense substitutions have already been established within the RASopathy VCEP framework, so PM5 is met at a moderate strength.

PP3Supporting

PP3 · supporting

Available computational evidence supports a damaging missense effect because the REVEL score is 0.821, which is above the KRAS VCEP PP3 threshold of 0.7; SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework; Rule14 applies.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/249272 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16042 alleles, homozygotes = 0).

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

No screenshot for this evidence

Computational predictions

Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · PP3 →

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB classifies this variant as Oncogenic; biological effect: Gain-of-function.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen KRAS VCEP v2.3.0, with the data and sources behind each one.

28 criteria with recorded statuses: 4 met · 4 not met · 9 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

The KRAS c.34G>C (p.Gly12Arg, p.G12R) variant has been observed in somatic cancers in COSMIC (COSV55497582; n=1720) and has been reported in ClinVar with pathogenic and likely pathogenic clinical submissions.

This variant is absent from population controls, with 0/249272 alleles in gnomAD v2.1 and no observation in gnomAD v4.1, which supports PM2 and argues against BA1 and BS1.

Available functional evidence is consistent with an activating KRAS effect, and OncoKB classifies this variant as oncogenic with gain-of-function, but the curated RASopathy VCEP materials did not provide sufficient approved variant-specific assay evidence to apply PS3.

This missense change affects codon 12 within the KRAS P-loop domain, and computational data are consistent with a damaging missense effect, with REVEL 0.821 and no predicted splice disruption by SpliceAI (maximum delta score 0.00).

Met · 4

PM1 ModerateThis variant affects codon 12 within the KRAS P-loop functional domain, which lies in the VCEP-defined PM1 region spanning amino acids 10 to 17, supporting PM1 at a moderate strength. Details ▾Hide ▴

Rule

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).

Evidence considered

p.(Gly12Arg) affects amino acid 12.
KRAS P-loop domain is defined as amino acids 10-17 in the VCEP PM1 materials.

Sources

cspec ↗vcep_a_l_i_g_n_m_e_n_t___w_i_t_h___p_m_1___d_o_m_a_i_n_s___p_p_t_x

PM2 SupportingThis variant is absent from population controls in gnomAD, with 0/249272 alleles in gnomAD v2.1 and no observation in gnomAD v4.1, meeting the KRAS VCEP PM2_Supporting rule. Details ▾Hide ▴

Rule

The variant must be absent from controls (gnomAD).

Evidence considered

gnomAD v2.1: 0/249272 alleles
gnomAD v4.1: absent

Sources

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PM5 ModerateThis missense variant affects codon 12, where other pathogenic missense substitutions have already been established within the RASopathy VCEP framework, so PM5 is met at a moderate strength. Details ▾Hide ▴

Rule

1 [likely] pathogenic residue change at the same codon.

Evidence considered

Codon 12 is an established pathogenic residue under the KRAS/RASopathy specification.
The VCEP functional-study table lists pathogenic same-codon or analogous codon-12 control substitutions in RAS genes.

Still missing

Specific same-codon proband counts were not available to assess PM5_Strong.

Sources

cspec ↗vcep_s_v_i___r_a_s_o_p_a_t_h_y___v_c_e_p___v_2___a_p_p_r_o_v_e_d___f_u_n_c_t_i_o_n_a_l___s_t_u_d_i_e_s

PP3 SupportingAvailable computational evidence supports a damaging missense effect because the REVEL score is 0.821, which is above the KRAS VCEP PP3 threshold of 0.7; SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴

Rule

For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.

Evidence considered

REVEL score 0.821
SpliceAI max delta score 0.00

Sources

cspec ↗spliceai ↗

Not met · 4 · evaluated, threshold not reached

PS4 This variant has been observed in somatic cancers and is reported in ClinVar, but no germline RASopathy case-count or point-based evidence was identified to meet the KRAS VCEP PS4 requirements. Details ▾Hide ▴

Evidence considered

COSMIC COSV55497582 somatic count 1720
ClinVar shows 3 pathogenic and 1 likely pathogenic submissions

Still missing

Proband counts and phenotype-based PS4 point assignments were not available.

Sources

cspec ↗clinvar ↗

BA1 Population frequency is below the BA1 threshold. The variant was seen 0/249272 alleles in gnomAD v2.1 (0.00000%) and was absent from gnomAD v4.1, which is below the KRAS BA1 threshold of 0.05%. Details ▾Hide ▴

Rule

GnomAD filtering allele frequency ≥0.05%.

Evidence considered

gnomAD v2.1 total AF 0.0 (0/249272)
Absent from gnomAD v4.1

Sources

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BS1 Population frequency is below the BS1 threshold. The variant was seen 0/249272 alleles in gnomAD v2.1 (0.00000%) and was absent from gnomAD v4.1, which is below the KRAS BS1 threshold of 0.025%. Details ▾Hide ▴

Rule

GnomAD filtering allele frequency ≥0.025%.

Evidence considered

gnomAD v2.1 total AF 0.0 (0/249272)
Absent from gnomAD v4.1

Sources

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP4 Available computational evidence does not support BP4 because the REVEL score is 0.821, which is above the benign BP4 threshold of 0.3. Details ▾Hide ▴

Rule

For missense variants: REVEL ≤0.3.

Evidence considered

REVEL score 0.821

Sources

cspec ↗

Not assessed · 9 · no assessment recorded

PS1 No evidence was identified showing the same amino acid change established as pathogenic from a different nucleotide change, so PS1 could not be assessed. Details ▾Hide ▴

Still missing

An independently established same-amino-acid alternate-nucleotide pathogenic variant was not identified.

Sources

cspec ↗

PS2 No confirmed de novo occurrence data were identified, so PS2 could not be assessed. Details ▾Hide ▴

Still missing

Confirmed maternity and paternity data were not available.

PS3 Available functional data support an activating effect in cancer systems, but no approved RASopathy VCEP functional assay evidence sufficient to apply PS3 for this specific variant was identified from the curated materials. Details ▾Hide ▴

Evidence considered

OncoKB classifies KRAS G12R as oncogenic with gain-of-function.
Cancer-focused studies describe altered KRAS signaling for G12R
but these were not sufficient for PS3 under the RASopathy VCEP framework.

Still missing

Variant-specific evidence meeting the approved RASopathy assay framework was not identified.

Sources

oncokb ↗vcep_s_v_i___r_a_s_o_p_a_t_h_y___v_c_e_p___v_2___a_p_p_r_o_v_e_d___f_u_n_c_t_i_o_n_a_l___s_t_u_d_i_e_sPMID:23455880 ↗PMID:26037647 ↗PMID:32792368 ↗

PM6 No assumed de novo data were identified, so PM6 could not be assessed. Details ▾Hide ▴

Still missing

Parentage and de novo status data were not available.

PP1 No segregation data were identified, so PP1 could not be assessed. Details ▾Hide ▴

Still missing

Family segregation data were not available.

BS2 No data were identified showing this variant in an unaffected individual under the phenotypic specifications required for BS2, so BS2 could not be assessed. Details ▾Hide ▴

Still missing

Unaffected carrier data were not available.

BS4 No nonsegregation data were identified, so BS4 could not be assessed. Details ▾Hide ▴

Still missing

Family nonsegregation data were not available.

BP2 No data were identified showing this variant in cis or trans with another pathogenic RASopathy variant, so BP2 could not be assessed. Details ▾Hide ▴

Still missing

Phase and second-variant data were not available.

BP5 No alternative molecular explanation for the phenotype in another gene was identified, so BP5 could not be assessed. Details ▾Hide ▴

Still missing

Case-level alternate-diagnosis data were not identified.

Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis missense variant is not a null variant, and PVS1 is not applicable in the KRAS RASopathy specification for this change. Details ▾Hide ▴

Evidence considered

Variant is a missense substitution p.(Gly12Arg).
Variant does not fall into the generic null-variant buckets.

Sources

cspec ↗pvs1_gene_contextpvs1_variant_assessment

PM3 N/APM3 is not applicable in this KRAS RASopathy framework. Details ▾Hide ▴

Evidence considered

KRAS VCEP marks PM3 as not applicable.

Sources

cspec ↗

PM4 N/AThis is not an in-frame insertion, in-frame deletion, or stop-loss variant, so PM4 does not apply. Details ▾Hide ▴

Evidence considered

Single-nucleotide missense substitution

Sources

cspec ↗

PP2 N/APP2 is not applicable in this KRAS RASopathy framework. Details ▾Hide ▴

Evidence considered

KRAS VCEP marks PP2 as not applicable.

Sources

cspec ↗

PP4 N/APP4 is not applicable in this KRAS RASopathy framework. Details ▾Hide ▴

Evidence considered

KRAS VCEP marks PP4 as not applicable.

Sources

cspec ↗

PP5 N/APP5 is not used in this RASopathy VCEP framework. Details ▾Hide ▴

Evidence considered

KRAS VCEP marks PP5 as not applicable.

Sources

cspec ↗

BS3 N/ABS3 is not applicable in this KRAS RASopathy framework. Details ▾Hide ▴

Evidence considered

KRAS VCEP marks BS3 as not applicable.

Sources

cspec ↗

BP1 N/AThis is a missense variant, whereas BP1 in this framework is reserved for truncating variants in genes where gain-of-function missense changes are the primary disease mechanism. Details ▾Hide ▴

Evidence considered

Missense change p.(Gly12Arg)

Sources

cspec ↗

BP3 N/ABP3 is not applicable in this KRAS RASopathy framework because no relevant benign repetitive region is defined for this gene. Details ▾Hide ▴

Evidence considered

KRAS VCEP marks BP3 as not applicable.

Sources

cspec ↗

BP6 N/ABP6 is not used in this KRAS RASopathy framework. Details ▾Hide ▴

Evidence considered

KRAS VCEP marks BP6 as not applicable.

Sources

cspec ↗

BP7 N/AThis is a missense variant, not a synonymous, intronic, or non-coding change, so BP7 does not apply. Details ▾Hide ▴

Evidence considered

Missense change p.(Gly12Arg)

Sources

cspec ↗

Identifiers

Gene: KRAS
Transcript: NM_033360.2
Coding (HGVS c.): NM_033360.2:c.34G>C
Protein (HGVS p.): NP_203524.1:p.(Gly12Arg)
GRCh38: chr12:25245351 C>G
GRCh37: chr12:25398285 C>G

Gene diagram

Every interpreted variant in KRAS, mapped onto the exon structure of NM_033360.2. Select a row to find it on the plot.

KRASNM_033360.2

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in KRAS — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 0 / 249,272 alleles AF 0 · 0 homozygotes

By genetic ancestry

gnomAD v2.1

AF 0 · 0 / 249,272 alleles · 0 hom

No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Rule

For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.

Evidence considered

REVEL score 0.821
SpliceAI max delta score 0.00

Sources

cspec ↗spliceai ↗

BP4 Available computational evidence does not support BP4 because the REVEL score is 0.821, which is above the benign BP4 threshold of 0.3. Details ▾Hide ▴

Rule

For missense variants: REVEL ≤0.3.

Evidence considered

REVEL score 0.821

Sources

cspec ↗

BP7 N/AThis is a missense variant, not a synonymous, intronic, or non-coding change, so BP7 does not apply. Details ▾Hide ▴

Evidence considered

Missense change p.(Gly12Arg)

Sources

cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Captured SpliceAI source record Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

ClinVar

This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratory).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB classifies this variant as Oncogenic; biological effect: Gain-of-function.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55497582, n = 1720 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.