Variant rs121913530 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate

The NM_004985.5(KRAS):c.34G>T(p.Gly12Cys) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KRAS
NM_004985.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:7O:2

Conservation

PhyloP100: 7.89

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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 chr12-25245350-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

PP5

Variant 12-25245351-C-A is Pathogenic according to our data. Variant chr12-25245351-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12578.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-25245351-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRAS	NM_004985.5 linkuse as main transcript	c.34G>T	p.Gly12Cys	missense_variant	2/5	ENST00000311936.8	NP_004976.2	P01116-2A0A024RAV5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8 linkuse as main transcript	c.34G>T	p.Gly12Cys	missense_variant	2/5	1	NM_004985.5	ENSP00000308495.3		P01116-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7Other:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Lung carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 15, 2001

- -

Lung adenocarcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Salgia Laboratory, City of Hope

- -

not provided

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

- -

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

- -

Lung cancer

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University

- -

Gallbladder cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute of Medical Sciences, Banaras Hindu University

Oct 30, 2020

- -

RASopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 23, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly12 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17704260, 26242988). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KRAS function (PMID: 16051643). 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: 12578). 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 glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 12 of the KRAS protein (p.Gly12Cys). -

Neoplasm

Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Endometrial carcinoma

Other:1

not provided, no classification provided

literature only

Laboratory of Translational Genomics, National Cancer Institute

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

.;.;D;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.55

T;T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Uncertain

0.55

MutationAssessor

Uncertain

2.6

M;.;M;.

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-7.0

D;D;D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0060

D;D;D;D

Sift4G

Uncertain

0.022

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.90

MutPred

0.77

Gain of catalytic residue at V14 (P = 2e-04);Gain of catalytic residue at V14 (P = 2e-04);Gain of catalytic residue at V14 (P = 2e-04);Gain of catalytic residue at V14 (P = 2e-04);

MVP

0.98

MPC

2.8

ClinPred

0.99

GERP RS

5.7

Varity_R

0.94

gMVP

0.99

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over