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)
ClinVar Genomic variation as it relates to human health
NM_004985.5(KRAS):c.35G>A (p.Gly12Asp)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
13 out of 35 submissions contributed to this classification
Help
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.
35
Somatic
Clinical impact
Help
no assertion criteria provided. Learn more about how ClinVar calculates review status.
This classification is based on the single submission received
Help
The aggregate somatic clinical impact for this variant for one or more tumor types, using the AMP/ASCO/CAP terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
1
Somatic
Oncogenicity
Help
criteria provided, single submitter. Learn more about how ClinVar calculates review status.
Oncogenic
This classification is based on the single submission received
Help
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
Variant Details
- Identifiers
-
NM_004985.5(KRAS):c.35G>A (p.Gly12Asp)
Variation ID: 12582 Accession: VCV000012582.59
- 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 25, 2025 Apr 30, 2025 Somatic - Clinical impact Nov 15, 2025 Nov 15, 2025 Oct 10, 2024 Somatic - Oncogenicity Aug 11, 2024 Mar 11, 2025 Mar 4, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_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 - Protein change
- G12D
- Other names
- -
- Canonical SPDI
- NC_000012.12:25245349:C:T
-
Global minor allele
frequency (GMAF) HelpThe 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
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 | ||
|---|---|---|---|---|---|---|
| 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 |
530 | 592 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
no assertion criteria provided
|
Feb 7, 2019 | RCV000013411.21 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 10, 2012 | RCV000022799.16 | |
| Pathogenic (2) |
no assertion criteria provided
|
Oct 25, 2012 | RCV000029214.16 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 30, 2025 | RCV000029215.22 | |
| Pathogenic (2) |
no assertion criteria provided
|
Aug 28, 2014 | RCV000144969.19 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Jan 5, 2024 | RCV000144970.17 | |
| Pathogenic (2) |
no assertion criteria provided
|
Aug 28, 2014 | RCV000150896.16 | |
| Pathogenic (1) |
no assertion criteria provided
|
Aug 28, 2014 | RCV000150897.15 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Nov 3, 2023 | RCV000272938.35 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 30, 2018 | RCV000433573.12 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 7, 2024 | RCV000548006.13 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Nov 3, 2023 | RCV000585796.12 | |
|
Vascular Tumors Including Pyogenic Granuloma
|
Likely pathogenic (1) |
no assertion criteria provided
|
Feb 19, 2015 | RCV000662266.9 |
| Pathogenic (1) |
no assertion criteria provided
|
Nov 4, 2019 | RCV000856666.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 1, 2021 | RCV001799604.9 | |
| not provided (1) |
no classification provided
|
- | RCV001839445.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 10, 2012 | RCV002508117.8 | |
| association (1) |
no assertion criteria provided
|
- | RCV003327361.6 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 22, 2022 | RCV004018620.1 | |
|
Congenital Pulmonary Airway Malformations
|
Pathogenic (1) |
criteria provided, single submitter
|
Jul 19, 2022 | RCV004554600.1 |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 23, 2024 | RCV005007840.1 | |
| click to load more conditions click to collapse | ||||
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. |
Expand all rows
Collapse all rows
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
(Dec 22, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Not Provided |
GeneDx
Accession: SCV000329383.7
First in ClinVar: Dec 06, 2016 Last updated: Dec 31, 2022 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Oct 07, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
RASopathy |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000659085.2
First in ClinVar: Dec 26, 2017 Last updated: Mar 04, 2025 |
Comment:
show
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 12 of the KRAS protein (p.Gly12Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been reported in the literature as a somatic event (present in tissue from a lesion but not in non-lesional tissue or peripheral blood) in individuals with congenital cutaneous disorders (PMID: 20805368, 22683711, 23096712, 23255105, 26521233). KRAS p.Gly12Asp is a frequently occurring somatic variant in several different types of cancers, including lung, ovarian, endometrial and pancreatic (PMID: 26861459, 1875403, 24629489, 23174937). ClinVar contains an entry for this variant (Variation ID: 12582). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt KRAS function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KRAS function (PMID: 15093544, 25623042). For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Linear nevus sebaceous syndrome |
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001736991.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Pathogenic
(Jan 05, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Autoimmune lymphoproliferative syndrome type 4 |
3billion
Accession: SCV002318898.3
First in ClinVar: Apr 02, 2022 Last updated: Jun 29, 2025 |
Comment:
show
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 29493581). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.88 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012582 /3billion dataset / PMID: 21079152). Different missense changes at the same codon (p.Gly12Ala, p.Gly12Arg, p.Gly12Cys, p.Gly12Ser, p.Gly12Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012578, VCV000012579, VCV000012583, VCV000012584, VCV000045122, VCV001701193 /PMID: 17704260). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Platform type: exome sequencing
|
|
|
Pathogenic
(Aug 13, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
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:
show
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:
2
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
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 hemorrhage (present) , Headache (present)
Observation 2
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Macrocephaly (present) , Cerebral arteriovenous malformation (present) , Retinal vascular tortuosity (present)
|
|
|
Pathogenic
(Oct 05, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
RASopathy |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002601600.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Dec 01, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002821689.22
First in ClinVar: Jan 21, 2023 Last updated: Oct 25, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Nov 03, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cerebral arteriovenous malformation |
Clinical Genomics Laboratory, Washington University in St. Louis
Accession: SCV004176950.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Likely pathogenic
(Aug 22, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiovascular phenotype |
Ambry Genetics
Accession: SCV005023563.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jul 19, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Congenital Pulmonary Airway Malformations
|
New York Genome Center
Study: PrenatalSEQ
Accession: SCV005044128.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024 |
Comment:
show
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)
Observation 1
Collection method: clinical testing
Allele origin: de novo
Affected status: yes
Clinical Features:
Congenital pulmonary airway malformation (present) , Thickened nuchal skin fold (present) , Fetal ascites (present)
Test name: whole genome sequencing
Zygosity: Single Heterozygote
Age: 20-29 weeks gestation
Secondary finding: no
Number of individuals demonstrating mosaicism for the variant: 1
Platform name: NovaSeq 6000
|
|
|
Pathogenic
(Nov 03, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Not provided |
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005414064.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 1940
|
|
|
Pathogenic
(Feb 23, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cerebral arteriovenous malformation
Malignant tumor of urinary bladder Familial cancer of breast Linear nevus sebaceous syndrome Lung cancer Familial pancreatic carcinoma Toriello-Lacassie-Droste syndrome Acute myeloid leukemia Noonan syndrome 3 Gastric cancer Autoimmune lymphoproliferative syndrome type 4 Cardiofaciocutaneous syndrome 2
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. |
Fulgent Genetics, Fulgent Genetics
Accession: SCV005634967.1
First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely pathogenic
(Apr 30, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Linear nevus sebaceous syndrome |
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Accession: SCV006304919.1
First in ClinVar: Aug 16, 2025 Last updated: Aug 16, 2025 |
Comment:
show
Detected variant allele frequency: 2%. The following ACMG criteria has been used: PS2_su, PS3_su, PM1_m, PP2_su, PP3_m (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jun 10, 2012)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
PANCREATIC CARCINOMA, SOMATIC |
OMIM
Accession: SCV000033658.5
First in ClinVar: Apr 04, 2013 Last updated: Mar 12, 2022 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
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)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
GASTRIC CANCER, SOMATIC |
OMIM
Accession: SCV000033659.5
First in ClinVar: Apr 04, 2013 Last updated: Mar 12, 2022 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
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)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
EPIDERMAL NEVUS, SOMATIC |
OMIM
Accession: SCV000044088.5
First in ClinVar: Apr 04, 2013 Last updated: Mar 12, 2022 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
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)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
NEVUS SEBACEOUS, SOMATIC |
OMIM
Accession: SCV000051860.5
First in ClinVar: Apr 04, 2013 Last updated: Mar 12, 2022 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
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)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
SCHIMMELPENNING-FEUERSTEIN-MIMS SYNDROME, SOMATIC MOSAIC |
OMIM
Accession: SCV000051861.5
First in ClinVar: Apr 04, 2013 Last updated: Mar 12, 2022 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
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)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
JUVENILE MYELOMONOCYTIC LEUKEMIA, SOMATIC |
OMIM
Accession: SCV000191996.4
First in ClinVar: Nov 22, 2014 Last updated: Mar 12, 2022 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
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)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC |
OMIM
Accession: SCV000191997.4
First in ClinVar: Nov 22, 2014 Last updated: Mar 12, 2022 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
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)
|
|
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Pathogenic
(Aug 28, 2014)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Juvenile myelomonocytic leukemia |
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198478.2
First in ClinVar: Jan 30, 2015 Last updated: May 29, 2016 |
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: not provided
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Aug 28, 2014)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Non-small cell lung carcinoma |
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198479.2
First in ClinVar: Jan 30, 2015 Last updated: May 29, 2016 |
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: not provided
Number of individuals with the variant: 85
|
|
|
Pathogenic
(Aug 28, 2014)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Ovarian cancer |
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198480.2
First in ClinVar: Jan 30, 2015 Last updated: May 29, 2016 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: not provided
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Oct 25, 2012)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Nevus sebaceous |
Yale Center for Mendelian Genomics, Yale University
Accession: SCV000611562.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: yes
Zygosity: Single Heterozygote
|
|
|
Pathogenic
(Mar 06, 2018)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
ARTERIOVENOUS MALFORMATION OF THE BRAIN, SOMATIC
|
OMIM
Accession: SCV000693723.1
First in ClinVar: Mar 14, 2018 Last updated: Mar 14, 2018 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
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)
|
|
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Likely pathogenic
(Feb 19, 2015)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Vascular Tumors Including Pyogenic Granuloma
|
Yale Center for Mendelian Genomics, Yale University
Accession: SCV000784594.1
First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018 |
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: yes
Zygosity: Single Heterozygote
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Non-small cell lung carcinoma
(Somatic mutation)
|
Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center
Accession: SCV000882686.2
First in ClinVar: Mar 08, 2017 Last updated: Apr 13, 2025 |
Observation 1
Collection method: research
Allele origin: somatic
Affected status: yes
Age: 37-82 years
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: United States of America
|
|
|
Pathogenic
(Feb 07, 2019)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Familial pancreatic carcinoma
(Somatic mutation)
|
Laboratory for Clinical Genomics and Advanced Technology, Dartmouth-Hitchcock Medical Center
Accession: SCV000882700.3
First in ClinVar: Mar 08, 2017 Last updated: Aug 03, 2025 |
Comment:
show
Variant causes impairment of the intrinsic GTPase activity of KRAS and subsequent activation of downstream signaling pathways that drive cancer growth. (less)
Observation 1
Collection method: research
Allele origin: somatic
Affected status: yes
Clinical Features:
Neoplasm of the pancreas (present)
Comment on clinical features:
A 55-year-old woman presented with abdominal bloating for approximately one year. Imaging studies showed a cyst in the body of the pancreas with proximal pancreatic ductal dilation. An endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) was performed. Cytologic findings from the cyst fluid were consistent with a mucinous neoplastic cyst and the possibility of malignancy could not be entirely excluded. A KRAS mutation analysis was performed on the cyst fluid showed a KRAS G12D mutation in the cyst fluid. The patient subsequently underwent a distal subtotal pancreatectomy with splenectomy. Microscopic examination of the resected tissue revealed an intraductal papillary-mucinous neoplasm (IPMN) with an associated invasive carcinoma. KRAS testing on the resected tumor tissue confirmed the G12D mutation detected in the cyst fluid earlier.
Test name: Real-Time PCR
Age: 50-59 years
Sex: female
Comment on evidence:
"effect on catalytic protein function" was previously submitted as the functional consequence for NM_004985.4:c.35G>A, but without providing the result of a functional assay.
Platform type: PCR
Platform name: Idyllaâ„¢ System (Biocartis, Mechelen, Belgium)
Method: The Idylla™ assays a cartridge-based testing) use a real-time PCR chemistry based on PlexPrime™ and PlexZyme™ (also known as MNAzyme) technology (Mokany et al. 2010). With this technology, each primer is designed to have a 5’ target-recognition region, a short 3’ 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.
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|
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Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Cerebral arteriovenous malformation |
Arin Greene Laboratory, Boston Children's Hospital, Harvard Medical School
Accession: SCV000992585.2
First in ClinVar: Dec 16, 2019 Last updated: Apr 13, 2025 |
Observation:
5
Observation 1
Collection method: research
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Age: 10-19 years
Sex: female
Observation 2
Collection method: research
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Age: 10-19 years
Sex: female
Observation 3
Collection method: research
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Age: 10-19 years
Sex: male
Observation 4
Collection method: research
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Age: 10-19 years
Sex: male
Observation 5
Collection method: research
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Age: 10-19 years
Sex: male
|
|
|
Pathogenic
(Nov 04, 2019)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Primary low grade serous adenocarcinoma of ovary |
University Health Network, Princess Margaret Cancer Centre
Accession: SCV000999192.1
First in ClinVar: Nov 29, 2019 Last updated: Nov 29, 2019 |
Observation 1
Collection method: research
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
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 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 119
|
|
|
Pathogenic
(Mar 30, 2018)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Acute myeloid leukemia |
Hematopathology, The University of Texas M.D. Anderson Cancer Center
Accession: SCV001571657.2
First in ClinVar: Apr 24, 2021 Last updated: Apr 13, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Age: 60-69 years
Sex: female
|
|
|
Pathogenic
(May 01, 2021)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Capillary malformation-arteriovenous malformation 1 |
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:
2
Observation 1
Collection method: research
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
capillary malformation (present) , arteriovenous malformation (present)
Observation 2
Collection method: research
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
capillary malformation (present) , arteriovenous malformation (present)
|
|
|
association
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
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. |
Martignetti Lab, Icahn School of Medicine at Mount Sinai
Accession: SCV004035006.2
First in ClinVar: Sep 16, 2023 Last updated: Apr 13, 2025 |
Observation 1
Collection method: research
Allele origin: somatic
Affected status: yes
Clinical Features:
Atypical endometrial hyperplasia (present)
Age: 50-59 years
Sex: female
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
|
Encephalocraniocutaneous lipomatosis |
GeneReviews
Accession: SCV002099547.2
First in ClinVar: Mar 03, 2022 Last updated: Oct 01, 2022 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: unknown
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: unknown
|
|
Comment:
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 12 of the KRAS protein (p.Gly12Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been reported in the literature as a somatic event (present in tissue from a lesion but not in non-lesional tissue or peripheral blood) in individuals with congenital cutaneous disorders (PMID: 20805368, 22683711, 23096712, 23255105, 26521233). KRAS p.Gly12Asp is a frequently occurring somatic variant in several different types of cancers, including lung, ovarian, endometrial and pancreatic (PMID: 26861459, 1875403, 24629489, 23174937). ClinVar contains an entry for this variant (Variation ID: 12582). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt KRAS function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KRAS function (PMID: 15093544, 25623042). For these reasons, this variant has been classified as Pathogenic.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 29493581). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.88 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012582 /3billion dataset / PMID: 21079152). Different missense changes at the same codon (p.Gly12Ala, p.Gly12Arg, p.Gly12Cys, p.Gly12Ser, p.Gly12Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012578, VCV000012579, VCV000012583, VCV000012584, VCV000045122, VCV001701193 /PMID: 17704260). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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:
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 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:
reported for somatic cases only, for germline findings, please reassess
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.
Comment:
PP3, PM2, PS3, PS4
Comment:
Detected variant allele frequency: 2%. The following ACMG criteria has been used: PS2_su, PS3_su, PM1_m, PP2_su, PP3_m
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.
Comment:
Missense, Gain-of-function
Citations for germline classification of this variant
Help| 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 |
| Mosaic RASopathy due to KRAS variant G12D with segmental overgrowth and associated peripheral vascular malformations. | Schmidt VF | American journal of medical genetics. Part A | 2021 | PMID: 34114335 |
| 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 |
| KRAS G12D or G12V Mutation in Human Brain Arteriovenous Malformations. | Oka M | World neurosurgery | 2019 | PMID: 30902772 |
| High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations. | Hong T | Brain : a journal of neurology | 2019 | PMID: 30544177 |
| 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 |
| Clinical and Molecular Characteristics of NF1-Mutant Lung Cancer. | Redig AJ | Clinical cancer research : an official journal of the American Association for Cancer Research | 2016 | PMID: 26861459 |
| The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome. | Joyce S | European journal of human genetics : EJHG | 2016 | PMID: 26242988 |
| KRAS G12D mosaic mutation in a Chinese linear nevus sebaceous syndrome infant. | Wang H | BMC medical genetics | 2015 | PMID: 26521233 |
| Somatic Activating RAS Mutations Cause Vascular Tumors Including Pyogenic Granuloma. | Lim YH | The Journal of investigative dermatology | 2015 | PMID: 25695684 |
| NFATc1 Links EGFR Signaling to Induction of Sox9 Transcription and Acinar-Ductal Transdifferentiation in the Pancreas. | Chen NM | Gastroenterology | 2015 | PMID: 25623042 |
| KRAS mutational analysis in ductal adenocarcinoma of the pancreas and its clinical significance. | Miglio U | Pathology, research and practice | 2014 | PMID: 24629489 |
| Mosaic RASopathies. | Hafner C | Cell cycle (Georgetown, Tex.) | 2013 | PMID: 23255105 |
| Frequency of mutations and polymorphisms in borderline ovarian tumors of known cancer genes. | Stemke-Hale K | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2013 | PMID: 23174937 |
| Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus. | Levinsohn JL | The Journal of investigative dermatology | 2013 | PMID: 23096712 |
| 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 |
| 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 |
| Mosaicism for oncogenic G12D KRAS mutation associated with epidermal nevus, polycystic kidneys and rhabdomyosarcoma. | Bourdeaut F | Journal of medical genetics | 2010 | PMID: 20805368 |
| KRAS mutation analysis in ovarian samples using a high sensitivity biochip assay. | Auner V | BMC cancer | 2009 | PMID: 19358724 |
| 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 |
| 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 |
| Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations. | Matsuda K | Blood | 2007 | PMID: 17332249 |
| Germline KRAS mutations cause Noonan syndrome. | Schubbert S | Nature genetics | 2006 | PMID: 16474405 |
| 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 |
| 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 |
| Parental acceptability of treatments for children's hypercholesterolemia. | Reimers TM | Journal of behavioral medicine | 1991 | PMID: 1875403 |
| click to load more citations click to collapse | ||||
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. |
|---|---|---|---|---|
|
Oncogenic
criteria provided, single submitter
|
Mar 4, 2025 | RCV004668724.2 | ||
|
Tier I (Strong)
- prognostic
- better outcome
(1)
|
Oct 10, 2024 | RCV006250158.1 |
Submissions - Somatic
|
Clinical impact
Help
The submitted somatic clinical impact 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. |
Expand all rows
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. |
|---|
|
Tier I (Strong)
- Prognostic
-
better outcome (Oct 10, 2024)
C
Contributing to aggregate classification
|
no assertion criteria provided
|
Colorectal cancer |
Department of Clinical Biochemistry, Naestved Hospital
Accession: SCV006076878.1
First In ClinVar: Nov 15, 2025 Last updated: Nov 15, 2025 |
Observation: 1
Collection method: research
Allele origin: somatic
Affected status: unknown
Observation 1
Collection method: research
Allele origin: somatic
Affected status: unknown
|
|
|
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. |
Expand all rows
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
(Mar 04, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neoplasm |
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094257.2
First In ClinVar: Aug 11, 2024 Last updated: Mar 11, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
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:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 12 of the KRAS protein (p.Gly12Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been reported in the literature as a somatic event (present in tissue from a lesion but not in non-lesional tissue or peripheral blood) in individuals with congenital cutaneous disorders (PMID: 20805368, 22683711, 23096712, 23255105, 26521233). KRAS p.Gly12Asp is a frequently occurring somatic variant in several different types of cancers, including lung, ovarian, endometrial and pancreatic (PMID: 26861459, 1875403, 24629489, 23174937). ClinVar contains an entry for this variant (Variation ID: 12582). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt KRAS function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KRAS function (PMID: 15093544, 25623042). For these reasons, this variant has been classified as Pathogenic.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 29493581). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.88 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012582 /3billion dataset / PMID: 21079152). Different missense changes at the same codon (p.Gly12Ala, p.Gly12Arg, p.Gly12Cys, p.Gly12Ser, p.Gly12Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012578, VCV000012579, VCV000012583, VCV000012584, VCV000045122, VCV001701193 /PMID: 17704260). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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:
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 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:
reported for somatic cases only, for germline findings, please reassess
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.
Comment:
PP3, PM2, PS3, PS4
Comment:
Detected variant allele frequency: 2%. The following ACMG criteria has been used: PS2_su, PS3_su, PM1_m, PP2_su, PP3_m
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.
Comment:
Missense, Gain-of-function
Citations for somatic classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations. | Hunter JC | Molecular cancer research : MCR | 2015 | PMID: 26037647 |
| KRAS(G12D)- and BRAF(V600E)-induced transformation of murine pancreatic epithelial cells requires MEK/ERK-stimulated IGF1R signaling. | Appleman VA | Molecular cancer research : MCR | 2012 | PMID: 22871572 |
| Germline KRAS mutations cause Noonan syndrome. | Schubbert S | Nature genetics | 2006 | PMID: 16474405 |
Text-mined citations for rs121913529 ...
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Record last updated Nov 15, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.