12-25227341-T-G

Variant names:

• chr12-25227341-T-G
• rs17851045
• NM_033360.4:c.183A>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS1 PM1 PM2 PM5 PP2 PP3 PP5

The NM_033360.4(KRAS):​c.183A>C​(p.Gln61His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q61R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRAS NM_033360.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2 O:2
• Conservation: PhyloP100: 2.81
• Publications: 1586 publications found

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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, PanelApp Australia
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS1: Transcript NM_033360.4 (KRAS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_033360.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-25227342-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45115.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 65 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 2.3177 (below the threshold of 3.09). Trascript score misZ: 2.7433 (below the threshold of 3.09). GenCC associations: The gene is linked to cardiofaciocutaneous syndrome, cardiofaciocutaneous syndrome 2, Noonan syndrome 3, Noonan syndrome, Costello syndrome, linear nevus sebaceous syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.757
• PP5: Variant 12-25227341-T-G is Pathogenic according to our data. Variant chr12-25227341-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 177881.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033360.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	NM_033360.4	MANE Plus Clinical	c.183A>C	p.Gln61His	missense	Exon 3 of 6	NP_203524.1
	KRAS	NM_004985.5	MANE Select	c.183A>C	p.Gln61His	missense	Exon 3 of 5	NP_004976.2
	KRAS	NM_001369786.1		c.183A>C	p.Gln61His	missense	Exon 3 of 6	NP_001356715.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	ENST00000256078.10	TSL:1 MANE Plus Clinical	c.183A>C	p.Gln61His	missense	Exon 3 of 6	ENSP00000256078.5
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.183A>C	p.Gln61His	missense	Exon 3 of 5	ENSP00000308495.3
	KRAS	ENST00000685328.1		c.183A>C	p.Gln61His	missense	Exon 3 of 5	ENSP00000508921.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251308 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Colorectal cancer Pathogenic:1

Jan 01, 2023

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS1, PM1, PM5, PP5, PM2, PP3

not provided Pathogenic:1

Jan 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Juvenile myelomonocytic leukemia Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Non-small cell lung carcinoma Pathogenic:1

Aug 28, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory

Cardiovascular phenotype Uncertain:1

Nov 10, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q61H variant (also known as c.183A>C), located in coding exon 2 of the KRAS gene, results from an A to C substitution at nucleotide position 183. The glutamine at codon 61 is replaced by histidine, an amino acid with highly similar properties. Somatic mutations impacting codon 61 of the KRAS gene are frequently observed in multiple cancer types; the p.Q61H variant is often identified in colorectal and lung adenocarcinomas as well as hematopoetic/lymphatic neoplasms (Prior IA et al. Cancer Res 2012;72(10):2457-67). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

RASopathy Uncertain:1

Oct 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRAS protein function. ClinVar contains an entry for this variant (Variation ID: 177881). This variant has not been reported in the literature in individuals affected with KRAS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 61 of the KRAS protein (p.Gln61His).

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary intracranial sarcoma, DICER1-mutant Other:1

Jul 31, 2024

Molecular Pathology Unit, Bambino Gesu' Children's Hospital, IRCCS

Significance:

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency) and it is reported in Clinvar as conflicting of pathogenicity. This missense change has been observed as a somatic variant in an individual with Dicer1-sarcoma. SIFT Algorithms suggests that this variant is likely to be deleterius. OncoKB database reported this variant as: Oncogenic, Gain-of-function with FDA levels that makes the variant as Tier IIC

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		2.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.41	B
Vest4		0.73
MutPred		0.66		Gain of catalytic residue at A59 (P = 0)
MVP		0.90
MPC		1.9
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.97
gMVP		0.94
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs17851045; hg19: chr12-25380275; COSMIC: COSV55498802; COSMIC: COSV55498802;