12-25245350-C-T

Position:

chr12-25245350-C-T

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. G12R) has been classified as Likely 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:36O: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 hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_004985.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-25245351-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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/exons	MANE	UniProt
KRAS	NM_033360.4 linkuse as main transcript	c.35G>A	p.Gly12Asp	missense_variant	2/6	ENST00000256078.10
KRAS	NM_004985.5 linkuse as main transcript	c.35G>A	p.Gly12Asp	missense_variant	2/5	ENST00000311936.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRAS	ENST00000256078.10 linkuse as main transcript	c.35G>A	p.Gly12Asp	missense_variant	2/6	1	NM_033360.4	A1	P01116-1
KRAS	ENST00000311936.8 linkuse as main transcript	c.35G>A	p.Gly12Asp	missense_variant	2/5	1	NM_004985.5	P4	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:36Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2022	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) -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Aug 13, 2021	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

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 10, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	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. -

Cerebral arteriovenous malformation

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 06, 2018	- -
Pathogenic, no assertion criteria provided	research	Arin Greene Laboratory, Boston Children's Hospital, Harvard Medical School	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Nov 03, 2023	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. -

Non-small cell lung carcinoma

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 28, 2014	- -
Pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	Mar 10, 2016	- -
Pathogenic, no assertion criteria provided	research	Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center	-	- -

Carcinoma of pancreas

Pathogenic:2Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 10, 2012	- -
not provided, no classification provided	literature only	Database of Curated Mutations (DoCM)	Mar 10, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratory for Clinical Genomics and Advanced Technology, Dartmouth-Hitchcock Medical Center	Feb 07, 2019	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

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 10, 2012	- -
Pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Oct 25, 2012	- -

Ovarian neoplasm

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 28, 2014	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). -
Pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	Oct 02, 2014	- -

Acute myeloid leukemia

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Hematopathology, The University of Texas M.D. Anderson Cancer Center	Mar 30, 2018	- -
Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	Oct 02, 2014	- -

Juvenile myelomonocytic leukemia

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 28, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 10, 2012	- -

RASopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 30, 2017	This sequence change replaces glycine with aspartic acid at codon 12 of the KRAS protein (p.Gly12Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs121913529, ExAC 0.01%). 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)Â¬â€ in individuals with nevus sebaceous syndrome (PMID: 23255105, 22683711, 23096712, 26521233). It was also observed in a child with epidermal nevus, polycystic kidneys, rhabdomyosarcoma and growth retardation (PMID: 20805368). In one family this variant was found in an infant with severe Schimmelpenning syndrome, whereas the monozygotic twin brother was unaffected showing that this variant in the affected individual was due to a postzygotic somatic event (PMID: 22683711, 23255105). ClinVar contains an entry for this variant (Variation ID: 12582). 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). Experimental studies using mouse knock-in models have shown that this missense change results in the activation of KRAS and increase in proliferation of mouse embryonic cells. In addition, pancreatic tissue from mice expressing this variant show de-differentiation and activation of signaling factors that initiate pancreatic cancer (PMID: 15093544, 25623042). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 05, 2022	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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 10, 2012

- -

Lung carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Mar 10, 2016

- -

Vascular Tumors Including Pyogenic Granuloma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Feb 19, 2015

- -

Gastric cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 10, 2012

- -

Primary low grade serous adenocarcinoma of ovary

Pathogenic:1

Pathogenic, no assertion criteria provided

research

University Health Network, Princess Margaret Cancer Centre

Nov 04, 2019

- -

Capillary malformation-arteriovenous malformation 1

Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

May 01, 2021

- -

Epidermal nevus

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 10, 2012

- -

Congenital Pulmonary Airway Malformations

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Jul 19, 2022

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2022

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

Thyroid tumor

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

Neoplasm of the large intestine

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

Encephalocraniocutaneous lipomatosis

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Atypical endometrial hyperplasia;C1516855:Endometrial hyperplasia without atypia

Other:1

association, no assertion criteria provided

research

Martignetti Lab, Icahn School of Medicine at Mount Sinai

- -

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

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;.

MutationTaster

Benign

1.0

D;D;D;D

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