Genetic Variant KRAS:p.Gly12Cys (chr12-25245351-C-A) – ACMG Classification: Pathogenic (27 pts)

Variant summary

Our verdict is The variant received 27 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_Very_StrongO3_ModerateO4_ModerateO5_SupportingO6_SupportingO7_StrongO8_Supporting

The NM_004985.5(KRAS):c.34G>T (p.Gly12Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The gene KRAS is a known oncogene (CancerMine: 2 TSG, 2158 oncogene, 346 driver citations). The gene KRAS is a cancer driver gene (CancerMine: 2 TSG, 2158 oncogene, 346 driver citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.89). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV004501632: Experimental studies have shown that this missense change affects KRAS function (PMID:16051643).". A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.G12R: Pathogenic/Likely_pathogenic (ClinVar VariationId 12579, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G12= (synonymous): Likely_benign (ClinVar VariationId 1734094, 1 star); p.G12= (synonymous): Likely_benign (ClinVar VariationId 4859020, 1 star); p.G12= (synonymous): Likely_benign (ClinVar VariationId 1734090, 1 star) This variant is listed in the SVIG-UK Canonical Variants List — a curated registry of well-established oncogenic variants (O1 criterion, stand-alone Oncogenic). This exact variant is established as oncogenic in: ClinVar, CGI (Cancer Genome Interpreter). The variant position is a cancer hotspot (cancerhotspots.org): 2910 samples carry this exact amino acid change out of 32010 samples with a variant at this residue. The variant has been observed in cBioPortal in 5927 samples across 145 studies and 134 cancer types; somatic enrichment level: MODERATE (Observed in many cases across multiple studies/cancer contexts.). This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Juvenile myelomonocytic leukemia (jmml); it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: not found (cov: 32)

Consequence

KRAS
NM_004985.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:7O:6

Conservation

PhyloP100: 7.89

Publications

1667 publications found

Variant links:

Genes affected

KRAS (HGNC:6407): (KRas proto-oncogene, GTPase) This gene, a Kirsten ras oncogene homolog from the mammalian ras gene family, encodes a protein that is a member of the small GTPase superfamily. A single amino acid substitution is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma. Alternative splicing leads to variants encoding two isoforms that differ in the C-terminal region. [provided by RefSeq, Jul 2008]

KRAS Gene-Disease associations (from GenCC):

cardiofaciocutaneous syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
Noonan syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Noonan syndrome 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
autoimmune lymphoproliferative syndrome type 4
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
cardiofaciocutaneous syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
linear nevus sebaceous syndrome
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

KRAS links:

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new If you want to explore the variant's impact on the transcript NM_004985.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for KRAS are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 27 points.

Show applied only (7)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		Variant on SVIG-UK Canonical Variants List — Stand-alone Oncogenic (O1); ClinVar oncogenic AND CGI oncogenic — two independent sources, Very Strong (O1); CGI exact DNA-change oncogenic — Strong (O1); ClinVar oncogenic/SCI T1 (single/no review, ★0–1) — Moderate (O1); O1 contributing sources (16.0 pts): SVIG-UK Canonical Variants List, ClinVar (somatic oncogenic/LO (★)), CGI (Cancer Genome Interpreter)
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 2.0) — Moderate (O4); cBioPortal: samples=5927 \| studies=145 \| cancer types=134 \| level=MODERATE \| points=2.0 \| reason: Observed in many cases across multiple studies/cancer contexts.
	O5Same location/impact as known oncogenic		Different AA at same residue with oncogenic evidence (or germline P/LP in TSG), or same AA change SCI Tier II Potential — Supporting (O5); ClinVar same-AA oncogenic/T1: false \| ClinVar same-AA SCI tier: — \| CGI same-AA oncogenic: false \| TSG: false \| ClinVar same-AA germline P/LP: true \| CIViC LOF: false \| ClinVar diff-AA oncogenic: true \| ClinVar diff-AA germline P/LP: true
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O7Mutational hotspot or critical domain		Strong hotspot (cancerhotspots.org): >50 total samples, ≥10 same AA change; Note: exclude MSK/TCGA-derived samples from cancerhotspots count to avoid double-counting with O4; cancerhotspots.org: total samples at AA position = 32010, same AA change = 2910; Exclude MSK/TCGA-derived samples from count to avoid double-counting with O4; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 16 pathogenic, 0 benign (OR vs. background: 165.0); Variant does not impact splicing — splice-hotspot path not applicable
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 3.09 (threshold ≥3.09 for constraint); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_004985.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
KRAS NM_033360.4	MANE Plus Clinical	c.34G>T p.Gly12Cys	missense	Exon 2 of 6	Prot: NP_203524.1 UniProt: P01116-1
KRAS NM_004985.5	MANE Select	c.34G>T p.Gly12Cys	missense	Exon 2 of 5	Prot: NP_004976.2
KRAS NM_001369786.1		c.34G>T p.Gly12Cys	missense	Exon 2 of 6	Prot: NP_001356715.1 UniProt: P01116-1

KRAS NM_033360.4

MANE Plus Clinical

HGVSc / HGVSpc.34G>Tp.Gly12Cys

Exon rankExon 2 of 6

missense

Prot: NP_203524.1UniProt: P01116-1

KRAS NM_004985.5

MANE Select

HGVSc / HGVSpc.34G>Tp.Gly12Cys

Exon rankExon 2 of 5

missense

Prot: NP_004976.2

KRAS NM_001369786.1

HGVSc / HGVSpc.34G>Tp.Gly12Cys

Exon rankExon 2 of 6

missense

Prot: NP_001356715.1UniProt: P01116-1

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
KRAS ENST00000256078.10	TSL:1MANE Plus Clinical	c.34G>T p.Gly12Cys	missense	Exon 2 of 6	Prot: ENSP00000256078.5 UniProt: P01116-1
KRAS ENST00000311936.8	TSL:1MANE Select	c.34G>T p.Gly12Cys	missense	Exon 2 of 5	Prot: ENSP00000308495.3 UniProt: P01116-2
KRAS ENST00000556131.2	TSL:1	c.34G>T p.Gly12Cys	missense	Exon 2 of 3	Prot: ENSP00000451856.1 UniProt: G3V4K2

KRAS ENST00000256078.10

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.34G>Tp.Gly12Cys

Exon rankExon 2 of 6

missense

Prot: ENSP00000256078.5UniProt: P01116-1

KRAS ENST00000311936.8

TSL:1MANE Select

HGVSc / HGVSpc.34G>Tp.Gly12Cys

Exon rankExon 2 of 5

missense

Prot: ENSP00000308495.3UniProt: P01116-2

KRAS ENST00000556131.2

TSL:1

HGVSc / HGVSpc.34G>Tp.Gly12Cys

Exon rankExon 2 of 3

missense

Prot: ENSP00000451856.1UniProt: G3V4K2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00	AC:0	Hom:	AN:249272	Cov:
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:55336	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Gallbladder cancer (1)

Lung adenocarcinoma (1)

Lung cancer (1)

Lung carcinoma (1)

Non-small cell lung carcinoma (1)

not provided (1)

RASopathy (1)

Adenocarcinoma of the large intestine (1)

Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (1)

Embryonal rhabdomyosarcoma (1)

Endometrial carcinoma (1)

Neoplasm (1)

Ovarian mucinous adenocarcinoma (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	32
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Pathogenic	0.97
GPN-Star LLR	N/A	-11
GPN-Star score	N/A	11
LIST_S2	Benign	0.55	T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.55	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Uncertain	2.6	M
PhyloP100	Pathogenic	7.9
popEVE	Uncertain	-4.8
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.022	D
Varity_R	N/A	0.94
VESM-3B	Benign	-14

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

14 no calibration

14 assays found for this variant.

No calibration: 14 assays (score only).

None of these data are clinically calibrated — they are not validated, so interpret them with great caution.

Protein level

binding fitness from KRAS-SOS1 bindingPCA of KRAS block1