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) 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.
ClinVar Genomic variation as it relates to human health
NM_004985.5(KRAS):c.35G>A (p.Gly12Asp)
Germline
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.
(40)
Help
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
40
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
Oncogenicity
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)
Help
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
1
criteria provided, single submitter
Variant Details
- Identifiers
-
NM_004985.5(KRAS):c.35G>A (p.Gly12Asp)
Variation ID: 12582 Accession: VCV000012582.43
- 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 Nov 24, 2024 Nov 3, 2023 Somatic - Oncogenicity Aug 11, 2024 Aug 11, 2024 Jul 31, 2024 - 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
-
Functional
consequence HelpThe 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) 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) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00000
- 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 |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
no assertion criteria provided
|
Feb 7, 2019 | RCV000013411.18 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 10, 2012 | RCV000022799.16 | |
| Pathogenic (2) |
no assertion criteria provided
|
Oct 25, 2012 | RCV000029214.16 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 22, 2022 | RCV000029215.19 | |
| Pathogenic (2) |
no assertion criteria provided
|
Aug 28, 2014 | RCV000144969.19 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 10, 2012 | RCV000144970.14 | |
| Pathogenic (3) |
no assertion criteria provided
|
Mar 10, 2016 | RCV000150896.14 | |
| Pathogenic (2) |
no assertion criteria provided
|
Oct 2, 2014 | RCV000150897.14 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Nov 3, 2023 | RCV000272938.27 | |
| Pathogenic (1) |
no assertion criteria provided
|
Oct 2, 2014 | RCV000426369.9 | |
| Pathogenic/Likely pathogenic (2) |
no assertion criteria provided
|
Mar 30, 2018 | RCV000433573.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
Oct 2, 2014 | RCV000443973.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Mar 10, 2016 | RCV000425250.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Nov 4, 2019 | RCV000856666.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 5, 2022 | RCV000548006.12 | |
| 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 |
| 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
|
- | RCV003327361.5 | |
| 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 |
| click to load more 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. |
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. |
|
|---|---|---|---|---|---|
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Pathogenic
(Jun 30, 2017)
|
criteria provided, single submitter
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) 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)
|
|
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Pathogenic
(Aug 13, 2021)
|
criteria provided, single submitter
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
(-)
|
criteria provided, single submitter
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 |
|
|
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Pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
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 |
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
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 |
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)
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|
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Pathogenic
(Dec 22, 2022)
|
criteria provided, single submitter
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)
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Pathogenic
(Nov 03, 2023)
|
criteria provided, single submitter
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)
|
|
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Likely pathogenic
(Aug 22, 2022)
|
criteria provided, single submitter
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
|
|
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Pathogenic
(Jul 19, 2022)
|
criteria provided, single submitter
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 |
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
|
|
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Pathogenic
(Dec 01, 2022)
|
criteria provided, single submitter
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
(Nov 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005414064.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP3, PM2, PS3, PS4
Number of individuals with the variant: 1940
|
|
|
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 |
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
|
|
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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 |
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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|
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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 |
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 |
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 |
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 |
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 |
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 |
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 |
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
(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 |
Number of individuals with the variant: 85
|
|
|
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 |
Number of individuals with the variant: 1
|
|
|
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 |
|
|
|
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 |
|
|
|
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 |
|
|
|
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 |
|
|
|
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 |
|
|
|
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 |
|
|
|
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 |
|
|
|
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 |
|
|
|
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 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.
|
|
|
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
(-)
|
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 |
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
|
|
|
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
|
|
|
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 |
|
|
|
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 |
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Comment:
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:
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:
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:
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:
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.
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
|
|
|
Laboratory for Clinical Genomics and Advanced Technology, Dartmouth-Hitchcock Medical Center
Accession: SCV000882700.1
|
|
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) 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:
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:
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:
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:
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 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 |
| 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 |
| 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 |
| Germline KRAS mutations cause Noonan syndrome. | Schubbert S | Nature genetics | 2006 | PMID: 16474405 |
| 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. |
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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. |
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Oncogenic
(Jul 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Neoplasm
Affected status: unknown
Allele origin:
somatic
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094257.1
First In ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
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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) 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:
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:
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:
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:
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
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Record last updated Nov 25, 2024
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.