12-25245351-C-T

Position:

chr12-25245351-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_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 allele was found at a frequency of 0.00000342 in 1,460,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12C) has been classified as Pathogenic.

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: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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 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 chr12-25245351-C-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.837

PP5

Variant 12-25245351-C-T is Pathogenic according to our data. Variant chr12-25245351-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-25245351-C-T is described in Lovd as [Pathogenic]. Variant chr12-25245351-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRAS	NM_004985.5 linkuse as main transcript	c.34G>A	p.Gly12Ser	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>A	p.Gly12Ser	missense_variant	2/5	1	NM_004985.5	ENSP00000308495.3		P01116-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460574

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726502

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Uncertain:1Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2023	Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17704260, 26242988, 24803665, 25691160, 32948832, 34851763, 29493581, 17875937, 35753512, 21228335, 18794081, 17384584, 15696205, 35197282, 36756182, 32816843, 18594010, 23406027, 23096712, 22683711, 18316791, 16618717, 26521233, 25157968) -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Uncertain significance, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -

Cardiofaciocutaneous syndrome 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PP3_Moderate+PS4_Moderate+PM6_Strong+PM5_Strong -

Gastric cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 15, 2007

- -

Juvenile myelomonocytic leukemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 15, 2007

- -

Non-small cell lung carcinoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 02, 2011

- -

Vascular malformation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Apr 10, 2024

A KRAS c.34G>A (p.Gly12Ser) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in the literature in multiple individuals with vascular malformations (Hou YCC et al., PMID: 36571464). This variant has been reported in more than 2,000 cases in the cancer database COSMIC (COSMIC ID: COSV55497461). Other variants in the same codon (p.Gly12Ala, p.Gly12Arg, p.Gly12Asp, p.Gly12Cys, p.Gly12Val) have been reported in the individuals affected with arteriovenous/vascular malformations and are considered pathogenic/likely pathogenic (Hou YCC et al., PMID: 36571464; Hong T et al., PMID: 30544177; Nava C et al., PMID: 17704260; Joyce S et al., PMID: 26242988; Nikolaev SI et al., PMID: 29298116; Fish JE et al., PMID: 32552404; Priemer DS et al., PMID: 31026472, ClinVar Variation ID: 45122, 12582, 12578, 177778, 12583). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to KRAS function. 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). The KRAS gene is defined by the ClinGen RASopathy expert panel (Gelb BD et al., PMID: 29493581) as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease. Based on available information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868) and the ClinGen RASopathy expert panel guidelines (Gelb BD et al., PMID: 29493581), this variant is classified as pathogenic. -

RASopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2021

ClinVar contains an entry for this variant (Variation ID: 12584). 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. This missense change has been observed in individuals with KRAS-related conditions (PMID: 17704260, 26242988). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the KRAS protein (p.Gly12Ser). For these reasons, this variant has been classified as 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: 20805368, 22683711, 23096712, 23255105, 26521233). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Neoplasm

Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Ovarian neoplasm

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

0.98

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

.;.;D;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

T;T;T;T

M_CAP

Benign

0.043

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

0.17

N;.;N;.

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-4.4

D;D;D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.027

D;D;D;D

Sift4G

Uncertain

0.014

D;D;D;T

Polyphen

0.56

P;.;P;.

Vest4

0.82

MutPred

0.76

Gain of catalytic residue at G12 (P = 0);Gain of catalytic residue at G12 (P = 0);Gain of catalytic residue at G12 (P = 0);Gain of catalytic residue at G12 (P = 0);

MVP

0.93

MPC

2.3

ClinPred

0.99

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.83

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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