rs17851045

Positions:

• 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 no assertion criteria provided P:2
• 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]

KRAS (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a chain GTPase KRas, N-terminally processed (size 184) 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/exons	MANE	Protein	UniProt
KRAS	NM_004985.5	c.183A>T	p.Gln61His	missense_variant	3/5	ENST00000311936.8	NP_004976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8	c.183A>T	p.Gln61His	missense_variant	3/5	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:2

Revision: no assertion criteria provided

Submissions by phenotype

Cerebral arteriovenous malformation Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

-

- -

Non-small cell lung carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 07, 2007

- -

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;