Genetic Variant KRAS:p.Gly12Ser (chr12-25245349-ACC-GCT) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is The variant received 9 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO5_ModerateO7_StrongO8_Supporting

The NM_004985.5(KRAS):c.34_36delGGTinsAGC (p.Gly12Ser) variant causes a missense change. 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). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.89). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.G12C: Likely_pathogenic (ClinVar VariationId 12578, 1 star) 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) The same amino acid change has been reported as oncogenic or likely oncogenic in a clinical somatic variant database. 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. This exact variant is curated in the UniProt human variants database as Pathogenic, 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

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.89

Publications

0 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: Likely_pathogenic. The variant received 9 points.

Show applied only (4)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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])
	O5Same location/impact as known oncogenic		Same AA change as established oncogenic variant (or germline P/LP in TSG) — Moderate (O5); ClinVar same-AA oncogenic/T1: true \| ClinVar same-AA SCI tier: — \| CGI same-AA oncogenic: true \| TSG: false \| ClinVar same-AA germline P/LP: true \| CIViC LOF: false \| ClinVar diff-AA oncogenic: true \| ClinVar diff-AA germline P/LP: true
	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.34_36delGGTinsAGC p.Gly12Ser	missense	N/A	Prot: NP_203524.1 UniProt: P01116-1
KRAS NM_004985.5	MANE Select	c.34_36delGGTinsAGC p.Gly12Ser	missense	N/A	Prot: NP_004976.2
KRAS NM_001369786.1		c.34_36delGGTinsAGC p.Gly12Ser	missense	N/A	Prot: NP_001356715.1 UniProt: P01116-1

KRAS NM_033360.4

MANE Plus Clinical

HGVSc / HGVSpc.34_36delGGTinsAGCp.Gly12Ser

Exon rankN/A

missense

Prot: NP_203524.1UniProt: P01116-1

KRAS NM_004985.5

MANE Select

HGVSc / HGVSpc.34_36delGGTinsAGCp.Gly12Ser

Exon rankN/A

missense

Prot: NP_004976.2

KRAS NM_001369786.1

HGVSc / HGVSpc.34_36delGGTinsAGCp.Gly12Ser

Exon rankN/A

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.34_36delGGTinsAGC p.Gly12Ser	missense	N/A	Prot: ENSP00000256078.5 UniProt: P01116-1
KRAS ENST00000311936.8	TSL:1MANE Select	c.34_36delGGTinsAGC p.Gly12Ser	missense	N/A	Prot: ENSP00000308495.3 UniProt: P01116-2
KRAS ENST00000556131.2	TSL:1	c.34_36delGGTinsAGC p.Gly12Ser	missense	N/A	Prot: ENSP00000451856.1 UniProt: G3V4K2

KRAS ENST00000256078.10

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.34_36delGGTinsAGCp.Gly12Ser

Exon rankN/A

missense

Prot: ENSP00000256078.5UniProt: P01116-1

KRAS ENST00000311936.8

TSL:1MANE Select

HGVSc / HGVSpc.34_36delGGTinsAGCp.Gly12Ser

Exon rankN/A

missense

Prot: ENSP00000308495.3UniProt: P01116-2

KRAS ENST00000556131.2

TSL:1

HGVSc / HGVSpc.34_36delGGTinsAGCp.Gly12Ser

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	7.9

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

The energetic and allosteric landscape for KRAS inhibition