chr12-25245350-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_004985.5(KRAS):c.35G>A(p.Gly12Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,744 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 Likely 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: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

KRAS
NM_004985.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:32O:3

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 14 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

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, 0.898

PP5

Variant 12-25245350-C-T is Pathogenic according to our data. Variant chr12-25245350-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-25245350-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5 link	c.35G>A	p.Gly12Asp	missense_variant	Exon 2 of 5	ENST00000311936.8	NP_004976.2	P01116-2A0A024RAV5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8 link	c.35G>A	p.Gly12Asp	missense_variant	Exon 2 of 5	1	NM_004985.5	ENSP00000308495.3		P01116-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249328

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134722

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460562

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726500

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000982

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:32Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2, PS3, PS4 -

Dec 22, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as a somatic variant in affected tissue from individuals with sebaceous nevi; the variant was not detected in blood or unaffected skin tissue of these individuals (Groesser et al., 2012; Levinsohn et al., 2013; Wang et al., 2015); Observed as a presumably somatic variant associated with malignancies, including various types of leukemia (Paulsson et al., 2008; Koorstra et al., 2008; Tyner et al., 2009; Zhang et al., 2011); Published functional studies demonstrate this variant affects GTP binding activity of the KRAS protein (Chen et al., 2013), and causes an increase in AKT phosphorylation (Petrova et al., 2016); 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; This variant is associated with the following publications: (PMID: 18813118, 23096712, 23437064, 24803665, 15093544, 19847165, 22264792, 21451123, 21502497, 18308936, 11323676, 26521233, 20805368, 19075190, 21680795, 30394973, 30936194, 30355600, 31836588, 29298116, 32246016, 30443000, 31891627, 33244099, 22683711, 27362559, 17875937, 29493581, 17910045) -

Aug 13, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a recurrent pathogenic variant that has previously been reported in several individuals with sporadic brain arteriovenous malformations (PMID: 29298116, 30902772, 30544177). The c.35G>A variant substitutes the glycine at codon 12 with aspartic acid. Experimental studies suggest that codon 12 substitutions lead to hyperactivation of the KRAS protein (PMID: 29298116). -

Linear nevus sebaceous syndrome

Pathogenic:3

Jun 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 22, 2022

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012582). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012583,VCV000012584, PMID:17704260). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.875>=0.6, 3CNET: 0.995>=0.75). A missense variant is a common mechanism . The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000040). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cerebral arteriovenous malformation

Pathogenic:3

Nov 03, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KRAS c.35G>A (p.Gly12Asp) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected with vascular malformations including numerous individuals with brain arteriovenous malformations (Nikolaev SI et al., PMID: 29298116; Lihua J et al., PMID: 29381910; Al-Olabi et al., PMID: 29461977; Goss JA et al., PMID: 31486960; Schmidt FV et al., PMID: 34114335; Mitchell BJ et al., PMID: 30394973). This variant has been reported in the ClinVar database as a pathogenic/likely pathogenic variant in both a somatic and germline state by multiple submitters (ClinVar ID: 12582) and in numerous cancer cases as a somatic variant in the cancer database COSMIC (COMIC ID: COSV55497369). This variant is only observed on 2/152,128 alleles in the general population (gnomAD v.3.1.2), indicating it is not a common variant. The KRAS c.35G>A (p.Gly12Asp) variant resides within the P-loop region 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 that this variant activates mitogen-activated protein kinase kinase 1 signaling pathway, leading to the formation of vascular malformation (Cistea IC et al., PMID: 23059812; Fish JE et al., PMID: 32552404; Janardhan HP et al., PMID: 32405640). The KRAS gene is defined by the ClinGen's 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 (Gelb BD et al., PMID: 29493581). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the KRAS c.35G>A (p.Gly12Asp) variant is classified as pathogenic. -

Mar 06, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Arin Greene Laboratory, Boston Children's Hospital, Harvard Medical School

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Carcinoma of pancreas

Pathogenic:2

Jun 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 07, 2019

Laboratory for Clinical Genomics and Advanced Technology, Dartmouth-Hitchcock Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Variant causes impairment of the intrinsic GTPase activity of KRAS and subsequent activation of downstream signaling pathways that drive cancer growth. -

Nevus sebaceous

Pathogenic:2

Jun 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 25, 2012

Yale Center for Mendelian Genomics, Yale University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Juvenile myelomonocytic leukemia

Pathogenic:2

Aug 28, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Non-small cell lung carcinoma

Pathogenic:2

Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Aug 28, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

RASopathy

Pathogenic:2

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 12 of the KRAS protein (p.Gly12Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been reported in the literature as a somatic event (present in tissue from a lesion but not in non-lesional tissue or peripheral blood) in individuals with congenital cutaneous disorders (PMID: 20805368, 22683711, 23096712, 23255105, 26521233). KRAS p.Gly12Asp is a frequently occurring somatic variant in several different types of cancers, including lung, ovarian, endometrial and pancreatic (PMID: 26861459, 1875403, 24629489, 23174937). ClinVar contains an entry for this variant (Variation ID: 12582). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt KRAS function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KRAS function (PMID: 15093544, 25623042). For these reasons, this variant has been classified as Pathogenic. -

Oct 05, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KRAS c.35G>A (p.Gly12Asp) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249328 control chromosomes (gnomAD). c.35G>A is a well classified pathogenic somatic mutation (ClinVar ID 2582). c.35G>A has been reported with varying levels of somatic mosaicism in individuals affected with anomalous pancreaticobiliary ductal union, epidermal nevus and Keratinocytic epidermal nevi and Schimmelpenning syndrome characterized by nevus sebaceous and extracutaneous abnormalities (Examples: Shimotake_2003, Bourdeaut_2010 and Hafner_2012, Groesser_2012). Experimental evidence have demonstrated that KRAS G12D is embryonically lethal in the mouse model and conditional expression in mouse embryonic fibroblasts causes enhanced proliferation and partial transformation consistent with a gain of function mechanism of disease (example: Tuveson_2004). A different variant affecting the same residue G12S is associated with Cardio-facio-cutaneous syndrome in HGMD (Nava_2007). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Autoimmune lymphoproliferative syndrome type 4

Pathogenic:1

Jun 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Vascular Tumors Including Pyogenic Granuloma

Pathogenic:1

Feb 19, 2015

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Malignant tumor of urinary bladder;C0023467:Acute myeloid leukemia;C0024623:Gastric cancer;C0242379:Lung cancer;C0346153:Familial cancer of breast;C0917804:Cerebral arteriovenous malformation;C1838329:Toriello-Lacassie-Droste syndrome;C1860991:Noonan syndrome 3;C2674723:Autoimmune lymphoproliferative syndrome type 4;C2931038:Familial pancreatic carcinoma;C3809005:Cardiofaciocutaneous syndrome 2;C4552097:Linear nevus sebaceous syndrome

Pathogenic:1

Feb 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastric cancer

Pathogenic:1

Jun 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Primary low grade serous adenocarcinoma of ovary

Pathogenic:1

Nov 04, 2019

University Health Network, Princess Margaret Cancer Centre

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Ovarian neoplasm

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

Somatic KRAS variants have been identified in up to 15% of cases of ovarian carcinoma, and Gly12Asp accounts for 40% of the identified KRAS variants (COSMIC 2010; Auner 2009). -

Capillary malformation-arteriovenous malformation 1

Pathogenic:1

May 01, 2021

Arin Greene Laboratory, Boston Children's Hospital, Harvard Medical School

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Acute myeloid leukemia

Pathogenic:1

Mar 30, 2018

Hematopathology, The University of Texas M.D. Anderson Cancer Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Epidermal nevus

Pathogenic:1

Jun 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Congenital Pulmonary Airway Malformations

Pathogenic:1

Jul 19, 2022

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35G>A variant in KRAS is an established pathogenic variant almost always exclusively found in tissue analysis of individuals with somatic cancers or tissue-limited phenotypes, and it has been deposited in ClinVar [ClinVar ID: 12582] as Pathogenic. The c.35G>A variant is observed in 5 alleles with 0 homozygote in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), which might be due to clonal hematopoesis of indeterminate potential or emerging/existing hematologic malignancies in variant carrying individuals in those databases. The c.35G>A variant in KRAS is located in exon 2 of this 5-exon gene, and is predicted to replace an evolutionarily conserved glycine amino acid with aspartate at position 12 (p.Gly12Asp) in the encoded protein. The p.Gly12Asp variant has been demonstrated to confer oncogenic potential via inhibiting the GTPase activity that result in continuous GTP-bound, active state [PMID: 11323676, 27096871]. Although another variant at codon 12 (p.Gly12Ser) has been reported in the germline of individuals with RASopathy phenotypes [PMID: 17704260, 26242988], p.Gly12Asp variant has not been reported constitutionally. The p.Gly12Asp variant has recently been identified in CPAM sections of individuals at less than 35% variant allele fraction (VAF) while the nearby unaffected lung tissue sections were found to be not carrying the p.Gly12Asp variant [PMID: 35794233]. The c.35G>A variant has been found at 28% VAF (13/47 reads) in this fetal sample, which might reflect the tissue-limited mosaicism of respiratory tract cells present in the amniotic fluid. Based on available evidence this de novo mosaic c.35G>A p.Gly12Asp variant identified in KRAS is classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Aug 22, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

reported for somatic cases only, for germline findings, please reassess -

Encephalocraniocutaneous lipomatosis

Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Atypical endometrial hyperplasia;C1516855:Endometrial hyperplasia without atypia

Other:1

Martignetti Lab, Icahn School of Medicine at Mount Sinai

Significance: association

Review Status: no assertion criteria provided

Collection Method: research

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

.;.;D;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.56

T;T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.7

M;.;M;.

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-5.3

D;D;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.010

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.39

B;.;P;.

Vest4

0.89

MutPred

0.77

Gain of catalytic residue at G13 (P = 0.001);Gain of catalytic residue at G13 (P = 0.001);Gain of catalytic residue at G13 (P = 0.001);Gain of catalytic residue at G13 (P = 0.001);

MVP

0.96

MPC

2.3

ClinPred

0.97

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.92

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