Genetic Variant KRAS:p.Gly12Ser (chr12-25245351-C-T) – ACMG Classification: Pathogenic (17 pts)

Variant summary

Our verdict is The variant received 17 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP2PP3_ModeratePP5_Strong

The NM_004985.5(KRAS):c.34G>A (p.Gly12Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.00000132, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. 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: "SCV005049528: "In support of this prediction, functional studies show that alterations in the "hotspot" codon 12 result in downstream MAPK/ERK pathway activation and tumor formation (Park JT, et al., PMID:25065594)."". 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) 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. 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)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

KRAS
NM_004985.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9U:1O:4

Conservation

PhyloP100: 7.89

Publications

7160 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 ACMG Germline Pathogenicity v2019

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 17 points.

Show applied only (7)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV005049528: "In support of this prediction, functional studies show that alterations in the "hotspot" codon 12 result in downstream MAPK/ERK pathway activation and tumor formation (Park JT, et al., PMID: 25065594)."
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 16 pathogenic, 0 benign (OR vs. background: 165.0).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000132 — very rare for AD/XL gene (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.G12C: Likely_pathogenic (ClinVar VariationId 12578, 1 star); Other variants at the same amino acid residue (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)
	PP2Missense in gene with low missense rate		Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 3.090). ClinVar shows strong pathogenic missense enrichment: 91 P/LP and 0 B/LB missense entries (ratio ∞).
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

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>A p.Gly12Ser	missense	Exon 2 of 6	Prot: NP_203524.1 UniProt: P01116-1
KRAS NM_004985.5	MANE Select	c.34G>A p.Gly12Ser	missense	Exon 2 of 5	Prot: NP_004976.2
KRAS NM_001369786.1		c.34G>A p.Gly12Ser	missense	Exon 2 of 6	Prot: NP_001356715.1 UniProt: P01116-1

KRAS NM_033360.4

MANE Plus Clinical

HGVSc / HGVSpc.34G>Ap.Gly12Ser

Exon rankExon 2 of 6

missense

Prot: NP_203524.1UniProt: P01116-1

KRAS NM_004985.5

MANE Select

HGVSc / HGVSpc.34G>Ap.Gly12Ser

Exon rankExon 2 of 5

missense

Prot: NP_004976.2

KRAS NM_001369786.1

HGVSc / HGVSpc.34G>Ap.Gly12Ser

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>A p.Gly12Ser	missense	Exon 2 of 6	Prot: ENSP00000256078.5 UniProt: P01116-1
KRAS ENST00000311936.8	TSL:1MANE Select	c.34G>A p.Gly12Ser	missense	Exon 2 of 5	Prot: ENSP00000308495.3 UniProt: P01116-2
KRAS ENST00000556131.2	TSL:1	c.34G>A p.Gly12Ser	missense	Exon 2 of 3	Prot: ENSP00000451856.1 UniProt: G3V4K2

KRAS ENST00000256078.10

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.34G>Ap.Gly12Ser

Exon rankExon 2 of 6

missense

Prot: ENSP00000256078.5UniProt: P01116-1

KRAS ENST00000311936.8

TSL:1MANE Select

HGVSc / HGVSpc.34G>Ap.Gly12Ser

Exon rankExon 2 of 5

missense

Prot: ENSP00000308495.3UniProt: P01116-2

KRAS ENST00000556131.2

TSL:1

HGVSc / HGVSpc.34G>Ap.Gly12Ser

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 6 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 Warning	AF: 0.00000342	AC:5	Hom:0	AN:1460574	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.00000756	AC:2	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:55336	Cov:

Showing 6 sources

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Cardiofaciocutaneous syndrome 2 (1)

Gastric cancer (1)

Juvenile myelomonocytic leukemia (1)

Non-small cell lung carcinoma (1)

RASopathy (1)

Vascular malformation (1)

Neoplasm (1)

Neuroblastoma (1)

Ovarian neoplasm (1)

Rhabdomyosarcoma (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	33
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-9.5
GPN-Star score	N/A	9.5
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.15	T
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Benign	0.17	N
PhyloP100	Pathogenic	7.9
popEVE	Uncertain	-4.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.4	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.6
REVEL	Pathogenic	0.79
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.014	D
Varity_R	N/A	0.83
VESM-3B	Benign	-12

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.020	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

The energetic and allosteric landscape for KRAS inhibition