VCV000012582.42 - ClinVar

NM_004985.5(KRAS):c.35G>A (p.Gly12Asp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(39)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Oncogenic

criteria provided, single submitter

Variant Details

Identifiers

NM_004985.5(KRAS):c.35G>A (p.Gly12Asp)

Variation ID: 12582 Accession: VCV000012582.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p12.1 12: 25245350 (GRCh38) [ NCBI UCSC ] 12: 25398284 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 22, 2014	Oct 20, 2024	Nov 3, 2023
Somatic - Oncogenicity	Aug 11, 2024	Aug 11, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004985.5:c.35G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004976.2:p.Gly12Asp	missense
NM_033360.4:c.35G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_203524.1:p.Gly12Asp	missense
NM_001369786.1:c.35G>A	NP_001356715.1:p.Gly12Asp	missense
NM_001369787.1:c.35G>A	NP_001356716.1:p.Gly12Asp	missense
NC_000012.12:g.25245350C>T
NC_000012.11:g.25398284C>T
NG_007524.2:g.10654G>A
LRG_344:g.10654G>A
LRG_344t1:c.35G>A	LRG_344p1:p.Gly12Asp
LRG_344t2:c.35G>A	LRG_344p2:p.Gly12Asp
	P01116:p.Gly12Asp

... more HGVS ... less HGVS

Protein change

G12D

Other names

Canonical SPDI

NC_000012.12:25245349:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

effect on catalytic protein function; Variation Ontology [ VariO:0008]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

Links

OMIM: 190070.0005 OMIM: 190070.0025 dbSNP: rs121913529 ClinGen: CA122538 UniProtKB: P01116#VAR_016026 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
KRAS		No evidence available	No evidence available	GRCh38 GRCh37	464	522

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Carcinoma of pancreas	Pathogenic (3)	no assertion criteria provided	Feb 7, 2019	RCV000013411.18
Epidermal nevus	Pathogenic (1)	no assertion criteria provided	Jun 10, 2012	RCV000022799.16
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 22, 2022	RCV000272938.26
Nevus sebaceous	Pathogenic (2)	no assertion criteria provided	Oct 25, 2012	RCV000029214.16
Linear nevus sebaceous syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 22, 2022	RCV000029215.19
Acute myeloid leukemia	Pathogenic/Likely pathogenic (2)	no assertion criteria provided	Mar 30, 2018	RCV000433573.10
Juvenile myelomonocytic leukemia	Pathogenic (2)	no assertion criteria provided	Aug 28, 2014	RCV000144969.19
Autoimmune lymphoproliferative syndrome type 4	Pathogenic (1)	no assertion criteria provided	Jun 10, 2012	RCV000144970.14
Non-small cell lung carcinoma	Pathogenic (3)	no assertion criteria provided	Mar 10, 2016	RCV000150896.14
Ovarian neoplasm	Pathogenic (2)	no assertion criteria provided	Oct 2, 2014	RCV000150897.14
Lung carcinoma	Likely pathogenic (1)	no assertion criteria provided	Mar 10, 2016	RCV000425250.9
Thyroid tumor	Pathogenic (1)	no assertion criteria provided	Oct 2, 2014	RCV000443973.9
RASopathy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 5, 2022	RCV000548006.12
Cerebral arteriovenous malformation	Pathogenic (3)	criteria provided, single submitter	Nov 3, 2023	RCV000585796.11
Vascular Tumors Including Pyogenic Granuloma	Likely pathogenic (1)	no assertion criteria provided	Feb 19, 2015	RCV000662266.9
Neoplasm of the large intestine	Pathogenic (1)	no assertion criteria provided	Oct 2, 2014	RCV000426369.9
Encephalocraniocutaneous lipomatosis	not provided (1)	no classification provided	-	RCV001839445.10
Primary low grade serous adenocarcinoma of ovary	Pathogenic (1)	no assertion criteria provided	Nov 4, 2019	RCV000856666.9
Congenital Pulmonary Airway Malformations	Pathogenic (1)	criteria provided, single submitter	Jul 19, 2022	RCV004554600.1
Capillary malformation-arteriovenous malformation 1	Pathogenic (1)	no assertion criteria provided	May 1, 2021	RCV001799604.9
Gastric cancer	Pathogenic (1)	no assertion criteria provided	Jun 10, 2012	RCV002508117.8
Atypical endometrial hyperplasia Endometrial hyperplasia without atypia	association (1)	no assertion criteria provided	-	RCV003327361.5
Cardiovascular phenotype	Likely pathogenic (1)	criteria provided, single submitter	Aug 22, 2022	RCV004018620.1
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jun 30, 2017)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RASopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000659085.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Comment: 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 … (more) 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. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Linear nevus sebaceous syndrome Affected status: yes Allele origin: somatic	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV001736991.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021
Pathogenic (Aug 13, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: somatic	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital Accession: SCV002525678.1 First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022	Comment: 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 … (more) 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). (less) Observation 1: Number of individuals with the variant: 1 Clinical Features: Arteriovenous malformation (present) , Intestinal malrotation (present) , Congenital diaphragmatic hernia (present) , Hypospadias (present) , Cardiac arrest (present) , Intracranial hemorrhage (present) , Subdural … (more) Arteriovenous malformation (present) , Intestinal malrotation (present) , Congenital diaphragmatic hernia (present) , Hypospadias (present) , Cardiac arrest (present) , Intracranial hemorrhage (present) , Subdural hemorrhage (present) , Headache (present) (less) Observation 2: Number of individuals with the variant: 1 Clinical Features: Macrocephaly (present) , Cerebral arteriovenous malformation (present) , Retinal vascular tortuosity (present)
Pathogenic (Dec 22, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329383.7 First in ClinVar: Dec 06, 2016 Last updated: Dec 31, 2022	Comment: 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 … (more) 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) (less)
Pathogenic (Nov 03, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cerebral arteriovenous malformation Affected status: yes Allele origin: somatic	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV004176950.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: 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 … (more) 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. (less)
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Linear nevus sebaceous syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV002318898.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (1) PubMed: 17704260 Comment: 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 … (more) 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. (less) Clinical Features: Blindness (present) , Cerebral atrophy (present) , Frontal bossing (present) , Headache (present) , Lymphadenopathy (present) , Nevus sebaceous (present) , Scoliosis (present)
Pathogenic (Oct 05, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	RASopathy Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002601600.1 First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022	Publications: PubMed (5) PubMed: 20805368‚ 22683711‚ 23255105‚ 12720172‚ 15093544 Comment: 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. … (more) 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. (less)
Likely pathogenic (Aug 22, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005023563.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: reported for somatic cases only, for germline findings, please reassess
Pathogenic (Jul 19, 2022)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Congenital Pulmonary Airway Malformations Affected status: yes Allele origin: de novo	New York Genome Center Study: PrenatalSEQ Accession: SCV005044128.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024	Publications: PubMed (1) PubMed: 35794233 Comment: 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, … (more) 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. (less) Clinical Features: Congenital pulmonary airway malformation (present) , Thickened nuchal skin fold (present) , Fetal ascites (present) Age: 20-29 weeks gestation Secondary finding: no
Pathogenic (Dec 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002821689.14 First in ClinVar: Jan 21, 2023 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Pathogenic (Aug 28, 2014)	no assertion criteria provided Method: clinical testing	Juvenile myelomonocytic leukemia Affected status: not provided Allele origin: somatic	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000198478.2 First in ClinVar: Jan 30, 2015 Last updated: May 29, 2016	Publications: PubMed (6) PubMed: 15696205‚ 15842656‚ 17332249‚ 17910045‚ 19047918‚ 19358724 Number of individuals with the variant: 1
Pathogenic (Aug 28, 2014)	no assertion criteria provided Method: clinical testing	Non-small cell lung carcinoma Affected status: not provided Allele origin: somatic	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000198479.2 First in ClinVar: Jan 30, 2015 Last updated: May 29, 2016	Publications: PubMed (6) PubMed: 15696205‚ 15842656‚ 17332249‚ 17910045‚ 19047918‚ 19358724 Number of individuals with the variant: 85
Pathogenic (Aug 28, 2014)	no assertion criteria provided Method: clinical testing	Ovarian cancer Affected status: not provided Allele origin: somatic	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000198480.2 First in ClinVar: Jan 30, 2015 Last updated: May 29, 2016	Publications: PubMed (6) PubMed: 15696205‚ 15842656‚ 17332249‚ 17910045‚ 19047918‚ 19358724 Comment: 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 … (more) 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). (less) Number of individuals with the variant: 3
Pathogenic (Mar 06, 2018)	no assertion criteria provided Method: literature only	ARTERIOVENOUS MALFORMATION OF THE BRAIN, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000693723.1 First in ClinVar: Mar 14, 2018 Last updated: Mar 14, 2018	Publications: PubMed (1) PubMed: 29298116 Comment on evidence: Using exome DNA sequencing and droplet digital PCR analysis, Nikolaev et al. (2018) identified a gly12-to-asp (G12D, c.35G-A) mutation in a total of 32 of … (more) Using exome DNA sequencing and droplet digital PCR analysis, Nikolaev et al. (2018) identified a gly12-to-asp (G12D, c.35G-A) mutation in a total of 32 of 72 arteriovenous malformations of the brain (BAVM; 108010), and in none of 21 paired blood samples. Patient samples included 39 from a main study group and 33 from an independent validation group. This and the G12V variant (190070.0026) were present in 2.4 to 4.0% of the sequence reads per sample. The G12D mutation drove MAPK-ERK activity in endothelial cells. (less)
Pathogenic (Feb 07, 2019)	no assertion criteria provided Method: research	Familial pancreatic carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Laboratory for Clinical Genomics and Advanced Technology, Dartmouth-Hitchcock Medical Center Accession: SCV000882700.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: Variant causes impairment of the intrinsic GTPase activity of KRAS and subsequent activation of downstream signaling pathways that drive cancer growth. Clinical Features: Neoplasm of the pancreas (present) Age: 50-59 years Sex: female Method: The Idyllaâ„¢ assays a cartridge-based testing) use a real-time PCR chemistry based on PlexPrimeâ„¢ and PlexZymeâ„¢ (also known as MNAzyme) technology (Mokany et al. 2010). With this technology, each primer is designed to have a 5â€™ target-recognition region, a short 3â€™ target-specific sequence complementary to the mutation of interest, and a distinct insert sequence that is mismatched to the target. This results in production of allele-specific amplicons that are detected in real time by allele-specific PlexZymeTM enzymes and a universal fluorescent probe, allowing for detection of multiple mutations in a single multiplex reaction.
Pathogenic (-)	no assertion criteria provided Method: research	Non-small cell lung carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center Accession: SCV000882686.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Age: 37-82 years Sex: mixed Ethnicity/Population group: Caucasian Geographic origin: United States of America
Pathogenic (Jun 10, 2012)	no assertion criteria provided Method: literature only	PANCREATIC CARCINOMA, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000033658.5 First in ClinVar: Apr 04, 2013 Last updated: Mar 12, 2022	Publications: PubMed (8) PubMed: 8439212‚ 7773929‚ 20805368‚ 22499344‚ 22683711‚ 20949522‚ 17332249‚ 21079152 Comment on evidence: Pancreatic Carcinoma, Somatic Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 … (more) Pancreatic Carcinoma, Somatic Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively. Gastric Cancer, Somatic Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D. Epidermal Nevus, Somatic Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway. Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017). Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy. Juvenile Myelomonocytic Leukemia, Somatic In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene. RAS-associated Autoimmune Leukoproliferative Disorder, Somatic In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene. (less)
Pathogenic (Jun 10, 2012)	no assertion criteria provided Method: literature only	EPIDERMAL NEVUS, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000044088.5 First in ClinVar: Apr 04, 2013 Last updated: Mar 12, 2022	Publications: PubMed (8) PubMed: 8439212‚ 7773929‚ 20805368‚ 22499344‚ 22683711‚ 20949522‚ 17332249‚ 21079152 Comment on evidence: Pancreatic Carcinoma, Somatic Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 … (more) Pancreatic Carcinoma, Somatic Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively. Gastric Cancer, Somatic Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D. Epidermal Nevus, Somatic Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway. Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017). Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy. Juvenile Myelomonocytic Leukemia, Somatic In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene. RAS-associated Autoimmune Leukoproliferative Disorder, Somatic In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene. (less)
Pathogenic (Jun 10, 2012)	no assertion criteria provided Method: literature only	NEVUS SEBACEOUS, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000051860.5 First in ClinVar: Apr 04, 2013 Last updated: Mar 12, 2022	Publications: PubMed (8) PubMed: 8439212‚ 7773929‚ 20805368‚ 22499344‚ 22683711‚ 20949522‚ 17332249‚ 21079152 Comment on evidence: Pancreatic Carcinoma, Somatic Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 … (more) Pancreatic Carcinoma, Somatic Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively. Gastric Cancer, Somatic Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D. Epidermal Nevus, Somatic Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway. Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017). Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy. Juvenile Myelomonocytic Leukemia, Somatic In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene. RAS-associated Autoimmune Leukoproliferative Disorder, Somatic In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene. (less)
Pathogenic (Jun 10, 2012)	no assertion criteria provided Method: literature only	RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000191997.4 First in ClinVar: Nov 22, 2014 Last updated: Mar 12, 2022	Publications: PubMed (8) PubMed: 8439212‚ 7773929‚ 20805368‚ 22499344‚ 22683711‚ 20949522‚ 17332249‚ 21079152 Comment on evidence: Pancreatic Carcinoma, Somatic Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 … (more) Pancreatic Carcinoma, Somatic Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively. Gastric Cancer, Somatic Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D. Epidermal Nevus, Somatic Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway. Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017). Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy. Juvenile Myelomonocytic Leukemia, Somatic In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene. RAS-associated Autoimmune Leukoproliferative Disorder, Somatic In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene. (less)
Pathogenic (Jun 10, 2012)	no assertion criteria provided Method: literature only	SCHIMMELPENNING-FEUERSTEIN-MIMS SYNDROME, SOMATIC MOSAIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000051861.5 First in ClinVar: Apr 04, 2013 Last updated: Mar 12, 2022	Publications: PubMed (8) PubMed: 8439212‚ 7773929‚ 20805368‚ 22499344‚ 22683711‚ 20949522‚ 17332249‚ 21079152 Comment on evidence: Pancreatic Carcinoma, Somatic Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 … (more) Pancreatic Carcinoma, Somatic Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively. Gastric Cancer, Somatic Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D. Epidermal Nevus, Somatic Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway. Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017). Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy. Juvenile Myelomonocytic Leukemia, Somatic In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene. RAS-associated Autoimmune Leukoproliferative Disorder, Somatic In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene. (less)
Pathogenic (Jun 10, 2012)	no assertion criteria provided Method: literature only	GASTRIC CANCER, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000033659.5 First in ClinVar: Apr 04, 2013 Last updated: Mar 12, 2022	Publications: PubMed (8) PubMed: 8439212‚ 7773929‚ 20805368‚ 22499344‚ 22683711‚ 20949522‚ 17332249‚ 21079152 Comment on evidence: Pancreatic Carcinoma, Somatic Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 … (more) Pancreatic Carcinoma, Somatic Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively. Gastric Cancer, Somatic Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D. Epidermal Nevus, Somatic Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway. Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017). Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy. Juvenile Myelomonocytic Leukemia, Somatic In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene. RAS-associated Autoimmune Leukoproliferative Disorder, Somatic In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene. (less)
Pathogenic (Jun 10, 2012)	no assertion criteria provided Method: literature only	JUVENILE MYELOMONOCYTIC LEUKEMIA, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000191996.4 First in ClinVar: Nov 22, 2014 Last updated: Mar 12, 2022	Publications: PubMed (8) PubMed: 8439212‚ 7773929‚ 20805368‚ 22499344‚ 22683711‚ 20949522‚ 17332249‚ 21079152 Comment on evidence: Pancreatic Carcinoma, Somatic Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 … (more) Pancreatic Carcinoma, Somatic Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively. Gastric Cancer, Somatic Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D. Epidermal Nevus, Somatic Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway. Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017). Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy. Juvenile Myelomonocytic Leukemia, Somatic In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene. RAS-associated Autoimmune Leukoproliferative Disorder, Somatic In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene. (less)
association (-)	no assertion criteria provided Method: research	Atypical endometrial hyperplasia Endometrial hyperplasia without atypia Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: yes Allele origin: somatic	Martignetti Lab, Icahn School of Medicine at Mount Sinai Accession: SCV004035006.1 First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023	Clinical Features: Atypical endometrial hyperplasia (present) Age: 50-59 years Sex: female
Pathogenic (Oct 02, 2014)	no assertion criteria provided Method: literature only	Thyroid tumor (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504483.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (4) PubMed: 19255327‚ 17384584‚ 19773371‚ 23406027 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000256078:c.35G>A
Pathogenic (Oct 02, 2014)	no assertion criteria provided Method: literature only	Neoplasm of the large intestine (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504481.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (8) PubMed: 16361624‚ 16618717‚ 19679400‚ 20921462‚ 18316791‚ 19114683‚ 20921465‚ 21228335 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000256078:c.35G>A
Likely pathogenic (Oct 02, 2014)	no assertion criteria provided Method: literature only	Acute myeloid leukemia (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504482.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (5) PubMed: 16434492‚ 2278970‚ 3122217‚ 19075190‚ 22407852 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000256078:c.35G>A
Pathogenic (Mar 10, 2016)	no assertion criteria provided Method: literature only	Non-small cell lung carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504486.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (3) PubMed: 18794081‚ 12460918‚ 19029981 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000256078:c.35G>A
Likely pathogenic (Mar 10, 2016)	no assertion criteria provided Method: literature only	Lung cancer (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504484.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (3) PubMed: 25044103‚ 23014527‚ 25157968 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000256078:c.35G>A
Pathogenic (Oct 02, 2014)	no assertion criteria provided Method: literature only	Ovarian neoplasm (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504485.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (2) PubMed: 21975775‚ 19018267 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000256078:c.35G>A
Pathogenic (Oct 25, 2012)	no assertion criteria provided Method: literature only	Nevus sebaceous Affected status: yes Allele origin: somatic	Yale Center for Mendelian Genomics, Yale University Accession: SCV000611562.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (1) PubMed: 23096712
Likely pathogenic (Feb 19, 2015)	no assertion criteria provided Method: literature only	Vascular Tumors Including Pyogenic Granuloma Affected status: yes Allele origin: somatic	Yale Center for Mendelian Genomics, Yale University Accession: SCV000784594.1 First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018	Publications: PubMed (1) PubMed: 25695684
Pathogenic (-)	no assertion criteria provided Method: research	Cerebral arteriovenous malformation Affected status: yes Allele origin: somatic	Arin Greene Laboratory, Boston Children's Hospital, Harvard Medical School Accession: SCV000992585.1 First in ClinVar: Dec 16, 2019 Last updated: Dec 16, 2019	Publications: PubMed (1) PubMed: 31891627 Observation 1: Number of individuals with the variant: 1 Age: 10-19 years Sex: female Observation 2: Number of individuals with the variant: 1 Age: 10-19 years Sex: female Observation 3: Number of individuals with the variant: 1 Age: 10-19 years Sex: male Observation 4: Number of individuals with the variant: 1 Age: 10-19 years Sex: male Observation 5: Number of individuals with the variant: 1 Age: 10-19 years Sex: male
Pathogenic (Nov 04, 2019)	no assertion criteria provided Method: research	Primary low grade serous adenocarcinoma of ovary Affected status: yes Allele origin: somatic	University Health Network, Princess Margaret Cancer Centre Accession: SCV000999192.1 First in ClinVar: Nov 29, 2019 Last updated: Nov 29, 2019	Number of individuals with the variant: 1
Pathogenic (Mar 30, 2018)	no assertion criteria provided Method: clinical testing	Acute myeloid leukemia Affected status: yes Allele origin: somatic	Hematopathology, The University of Texas M.D. Anderson Cancer Center Accession: SCV001571657.1 First in ClinVar: Apr 24, 2021 Last updated: Apr 24, 2021	Age: 60-69 years Sex: female
Pathogenic (May 01, 2021)	no assertion criteria provided Method: research	Capillary malformation-arteriovenous malformation 1 Affected status: yes Allele origin: somatic	Arin Greene Laboratory, Boston Children's Hospital, Harvard Medical School Accession: SCV001739511.1 First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022	Observation 1: Number of individuals with the variant: 1 Clinical Features: capillary malformation (present) , arteriovenous malformation (present) Observation 2: Number of individuals with the variant: 1 Clinical Features: capillary malformation (present) , arteriovenous malformation (present)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001550138.2 First in ClinVar: Apr 13, 2021 Last updated: Nov 29, 2022	Number of individuals with the variant: 119
not provided (-)	no classification provided Method: literature only	Encephalocraniocutaneous lipomatosis Affected status: unknown Allele origin: somatic	GeneReviews Accession: SCV002099547.2 First in ClinVar: Mar 03, 2022 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 30443000 BookShelf: NBK576966 BookShelf: NBK576966
not provided (Mar 10, 2016)	no classification provided Method: literature only	Carcinoma of pancreas (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504487.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 22025163 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000256078:c.35G>A
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Comment:

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.

Comment:

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).

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
effect on catalytic protein function (VariO:0008)	The Idyllaâ„¢ assays a cartridge-based testing) use a real-time PCR chemistry based on PlexPrimeâ„¢ and PlexZymeâ„¢ (also known as MNAzyme) technology (Mokany et al. 2010). With this technology, each primer is designed to have a 5â€™ target-recognition region, a short 3â€™ target-specific sequence complementary to the mutation of interest, and a distinct insert sequence that is mismatched to the target. This results in production of allele-specific amplicons that are detected in real time by allele-specific PlexZymeTM enzymes and a universal fluorescent probe, allowing for detection of multiple mutations in a single multiplex reaction.	Result not provided	Laboratory for Clinical Genomics and Advanced Technology, Dartmouth-Hitchcock Medical Center Accession: SCV000882700.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Defining the spatial landscape of KRAS mutated congenital pulmonary airway malformations: a distinct entity with a spectrum of histopathologic features.	Nelson ND	Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc	2022	PMID: 35794233
Encephalocraniocutaneous Lipomatosis.	Adam MP	-	2022	PMID: 35099867
Somatic mutations in intracranial arteriovenous malformations.	Goss JA	PloS one	2019	PMID: 31891627
Heterogeneous alteration of the ERBB3-MYC axis associated with MEK inhibitor resistance in a KRAS-mutated low-grade serous ovarian cancer patient.	Colombo I	Cold Spring Harbor molecular case studies	2019	PMID: 31836588
Exceptional responders with invasive mucinous adenocarcinomas: a phase 2 trial of bortezomib in patients with KRAS G12D-mutant lung cancers.	Drilon A	Cold Spring Harbor molecular case studies	2019	PMID: 30936194
A postzygotic KRAS mutation in a patient with Schimmelpenning syndrome presenting with lipomatosis, renovascular hypertension, and diabetes mellitus.	Nagatsuma M	Journal of human genetics	2019	PMID: 30443000
Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.	Nikolaev SI	The New England journal of medicine	2018	PMID: 29298116
Somatic Activating RAS Mutations Cause Vascular Tumors Including Pyogenic Granuloma.	Lim YH	The Journal of investigative dermatology	2015	PMID: 25695684
Prospective enterprise-level molecular genotyping of a cohort of cancer patients.	MacConaill LE	The Journal of molecular diagnostics : JMD	2014	PMID: 25157968
Phase II study of the GI-4000 KRAS vaccine after curative therapy in patients with stage I-III lung adenocarcinoma harboring a KRAS G12C, G12D, or G12V mutation.	Chaft JE	Clinical lung cancer	2014	PMID: 25044103
Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer.	Ho AL	The New England journal of medicine	2013	PMID: 23406027
Mosaic RASopathies.	Hafner C	Cell cycle (Georgetown, Tex.)	2013	PMID: 23255105
Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus.	Levinsohn JL	The Journal of investigative dermatology	2013	PMID: 23096712
Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers.	Dogan S	Clinical cancer research : an official journal of the American Association for Cancer Research	2012	PMID: 23014527
Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome.	Groesser L	Nature genetics	2012	PMID: 22683711
Keratinocytic epidermal nevi are associated with mosaic RAS mutations.	Hafner C	Journal of medical genetics	2012	PMID: 22499344
RAS mutations are frequent in FAB type M4 and M5 of acute myeloid leukemia, and related to late relapse: a study of the Japanese Childhood AML Cooperative Study Group.	Sano H	International journal of hematology	2012	PMID: 22407852
First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors.	Yap TA	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2011	PMID: 22025163
Epidermal growth factor receptor blockers for the treatment of ovarian cancer.	Haldar K	The Cochrane database of systematic reviews	2011	PMID: 21975775
Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study.	Bokemeyer C	Annals of oncology : official journal of the European Society for Medical Oncology	2011	PMID: 21228335
Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis.	Niemela JE	Blood	2011	PMID: 21079152
Discordance for Schimmelpenning-Feuerstein-Mims syndrome in monochorionic twins supports the concept of a postzygotic mutation.	Rijntjes-Jacobs EG	American journal of medical genetics. Part A	2010	PMID: 20949522
Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study.	Douillard JY	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2010	PMID: 20921465
Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer.	Peeters M	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2010	PMID: 20921462
Mosaicism for oncogenic G12D KRAS mutation associated with epidermal nevus, polycystic kidneys and rhabdomyosarcoma.	Bourdeaut F	Journal of medical genetics	2010	PMID: 20805368
Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma.	Hoftijzer H	European journal of endocrinology	2009	PMID: 19773371
Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer.	Neumann J	Pathology, research and practice	2009	PMID: 19679400
KRAS mutation analysis in ovarian samples using a high sensitivity biochip assay.	Auner V	BMC cancer	2009	PMID: 19358724
Phase II trial of sorafenib in metastatic thyroid cancer.	Kloos RT	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2009	PMID: 19255327
Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer.	Bokemeyer C	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2009	PMID: 19114683
High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients.	Tyner JW	Blood	2009	PMID: 19075190
Correlation of clinical features with the mutational status of GM-CSF signaling pathway-related genes in juvenile myelomonocytic leukemia.	Yoshida N	Pediatric research	2009	PMID: 19047918
Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers.	Engelman JA	Nature medicine	2008	PMID: 19029981
KRAS or BRAF mutation status is a useful predictor of sensitivity to MEK inhibition in ovarian cancer.	Nakayama N	British journal of cancer	2008	PMID: 19018267
Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma.	Riely GJ	Clinical cancer research : an official journal of the American Association for Cancer Research	2008	PMID: 18794081
Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.	Amado RG	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2008	PMID: 18316791
Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia.	Paulsson K	Genes, chromosomes & cancer	2008	PMID: 17910045
Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome.	Nava C	Journal of medical genetics	2007	PMID: 17704260
Hyperactive Ras in developmental disorders and cancer.	Schubbert S	Nature reviews. Cancer	2007	PMID: 17384584
Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations.	Matsuda K	Blood	2007	PMID: 17332249
KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer.	Lièvre A	Cancer research	2006	PMID: 16618717
Implications of NRAS mutations in AML: a study of 2502 patients.	Bacher U	Blood	2006	PMID: 16434492
Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma.	Rothenberg ML	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2005	PMID: 16361624
Somatic PTPN11 mutations in childhood acute myeloid leukaemia.	Tartaglia M	British journal of haematology	2005	PMID: 15842656
KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib.	Pao W	PLoS medicine	2005	PMID: 15696205
Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects.	Tuveson DA	Cancer cell	2004	PMID: 15093544
DPC-4 (Smad-4) and K-ras gene mutations in biliary tract epithelium in children with anomalous pancreaticobiliary ductal union.	Shimotake T	Journal of pediatric surgery	2003	PMID: 12720172
BRAF and RAS mutations in human lung cancer and melanoma.	Brose MS	Cancer research	2002	PMID: 12460918
Clinicopathologic significance of the K-ras gene codon 12 point mutation in stomach cancer. An analysis of 140 cases.	Lee KH	Cancer	1995	PMID: 7773929
Detection of point mutations in the Kirsten-ras oncogene provides evidence for the multicentricity of pancreatic carcinoma.	Motojima K	Annals of surgery	1993	PMID: 8439212
RAS gene mutations in childhood acute myeloid leukemia: a Pediatric Oncology Group study.	Vogelstein B	Genes, chromosomes & cancer	1990	PMID: 2278970
RAS gene mutations in acute and chronic myelocytic leukemias, chronic myeloproliferative disorders, and myelodysplastic syndromes.	Janssen JW	Proceedings of the National Academy of Sciences of the United States of America	1987	PMID: 3122217
http://docm.genome.wustl.edu/variants/ENST00000256078:c.35G>A	-	-	-	-
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Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Neoplasm		Oncogenic criteria provided, single submitter	Jul 31, 2024	RCV004668724.1

Submissions - Somatic

Oncogenicity Help The submitted oncogenicity classification for each SCV record. (Last evaluated)	Review Status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Tumor type Help The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Oncogenic

(Jul 31, 2024)

(ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022)

Method: clinical testing

Neoplasm

Affected status: unknown

Allele origin: somatic

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Accession: SCV005094257.1
First In ClinVar: Aug 11, 2024
Last updated: Aug 11, 2024

Comment:

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).

Comment:

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

Citations for somatic classification of this variant

There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs121913529 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_004985.5(KRAS):c.35G>A (p.Gly12Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Conditions - Somatic

Submissions - Somatic

Citations for somatic classification of this variant

Text-mined citations for rs121913529 ...