rs17851045

Variant names:

• chr12-25227341-T-A
• rs17851045
• NM_004985.5:c.183A>T

Your query was ambiguous. Multiple possible variants found:

• chr12-25227341-T-A
• chr12-25227341-T-C
• chr12-25227341-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_004985.5(KRAS):​c.183A>T​(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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q61L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRAS NM_004985.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 2.81

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a chain GTPase KRas (size 185) in uniprot entity RASK_HUMAN there are 29 pathogenic changes around while only 0 benign (100%) in NM_004985.5
• 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-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766
• PP5: Variant 12-25227341-T-A is Pathogenic according to our data. Variant chr12-25227341-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 45117.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-25227341-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5	c.183A>T	p.Gln61His	missense_variant	Exon 3 of 5	ENST00000311936.8	NP_004976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8	c.183A>T	p.Gln61His	missense_variant	Exon 3 of 5	1	NM_004985.5	ENSP00000308495.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Cerebral arteriovenous malformation Pathogenic:1

-

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Non-small cell lung carcinoma Pathogenic:1

Dec 07, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Vascular malformation Pathogenic:1

Aug 12, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A KRAS c.183A>T (p.Gln61His) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected with vascular malformations (Al-Olabi L et al., PMID: 29461977; Li H et al., PMID: 34530633; Hong T et al., PMID: 30544177; Nikolaev SI et al., PMID: 29298116). This variant has been reported in the ClinVar database as a pathogenic somatic variant by two submitters (ClinVar Variation ID: 45117). It is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. The KRAS c.183A>T (p.Gln61His) variant resides within the Switch II domain, amino acids 59-67, of KRAS that is defined as a critical functional domain (Gelb BD et al. PMID: 29493581). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to KRAS function. In support of this prediction, functional studies show increased ERK activation and transforming potential, indicating that this variant impacts protein function (Huynh MV et al., PMID: 35944066; Smith G et al., PMID: 20147967). The KRAS gene is defined by the ClinGen RASopathies expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease. Another variant in the same codon, c.183A>C (p.Gln61His), has been reported in multiple individuals affected with vascular malformations (Luo Su et al., PMID: 25219651; Al-Olabi et al, PMID: 29461977). Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), KRAS c.183A>T (p.Gln61His) variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
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;T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.41	B;B
Vest4		0.73
MutPred		0.66		Gain of catalytic residue at A59 (P = 0);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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs17851045; hg19: chr12-25380275; COSMIC: COSV55499223; COSMIC: COSV55499223;