The KRAS c.38G>A variant is predicted to result in the amino acid substitution p.Gly13Asp. This variant has been reported as a mosaic change in two patients with RAS-associated autoimmune leukoproliferative disorder, oculoectodermal syndrome/encephalocraniocutaneous lipomatosis, and an individual with myelodysplastic/myeloproliferative disease who was also positive for additional variants (Takagi et al. 2011. PubMed ID: 21063026; Peacock et al. 2015. PubMed ID: 25808193; Moog and Moog. 2022. PubMed ID: 35099867; Patient 2, Ismael et al. 2012. PubMed ID: 22571758). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_004985.5(KRAS):c.38G>A (p.Gly13Asp)
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.
(21)
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
21
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.38G>A (p.Gly13Asp)
Variation ID: 12580 Accession: VCV000012580.54
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12p12.1 12: 25245347 (GRCh38) [ NCBI UCSC ] 12: 25398281 (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 Aug 4, 2024 Nov 15, 2023 Somatic - Oncogenicity Aug 11, 2024 Aug 11, 2024 Jul 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004985.5:c.38G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004976.2:p.Gly13Asp missense NM_033360.4:c.38G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_203524.1:p.Gly13Asp missense NM_001369786.1:c.38G>A NP_001356715.1:p.Gly13Asp missense NM_001369787.1:c.38G>A NP_001356716.1:p.Gly13Asp missense NM_004985.4:c.38G>A NC_000012.12:g.25245347C>T NC_000012.11:g.25398281C>T NG_007524.2:g.10657G>A LRG_344:g.10657G>A LRG_344t1:c.38G>A LRG_344p1:p.Gly13Asp LRG_344t2:c.38G>A LRG_344p2:p.Gly13Asp P01116:p.Gly13Asp - Protein change
- G13D
- Other names
- -
- Canonical SPDI
- NC_000012.12:25245346:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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
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 |
463 | 520 | |
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 (1) |
no assertion criteria provided
|
Jul 1, 2015 | RCV000013409.11 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 10, 2016 | RCV000421576.3 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Nov 2, 2011 | RCV000038269.7 | |
| Pathogenic (1) |
no assertion criteria provided
|
Oct 2, 2014 | RCV000427102.2 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jul 1, 2015 | RCV000144967.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jul 1, 2015 | RCV000144968.9 | |
|
OCULOECTODERMAL SYNDROME, SOMATIC
|
Pathogenic (1) |
no assertion criteria provided
|
Jul 1, 2015 | RCV000791297.4 |
| Likely pathogenic (1) |
no assertion criteria provided
|
Oct 2, 2014 | RCV000431806.2 | |
| Pathogenic (1) |
no assertion criteria provided
|
Oct 2, 2014 | RCV000444192.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 19, 2023 | RCV001857340.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV001526657.3 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Sep 9, 2021 | RCV001092389.29 | |
|
KRAS-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Nov 15, 2023 | RCV004549358.1 |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 19, 2018 | RCV001266168.3 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
|
Jun 6, 2024 | RCV001813183.5 | |
| not provided (1) |
no classification provided
|
- | RCV001839444.3 | |
| 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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002016398.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Nov 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
KRAS-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004742495.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The KRAS c.38G>A variant is predicted to result in the amino acid substitution p.Gly13Asp. This variant has been reported as a mosaic change in two … (more)
The KRAS c.38G>A variant is predicted to result in the amino acid substitution p.Gly13Asp. This variant has been reported as a mosaic change in two patients with RAS-associated autoimmune leukoproliferative disorder, oculoectodermal syndrome/encephalocraniocutaneous lipomatosis, and an individual with myelodysplastic/myeloproliferative disease who was also positive for additional variants (Takagi et al. 2011. PubMed ID: 21063026; Peacock et al. 2015. PubMed ID: 25808193; Moog and Moog. 2022. PubMed ID: 35099867; Patient 2, Ismael et al. 2012. PubMed ID: 22571758). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Nov 02, 2011)
|
criteria provided, single submitter
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: SCV000061938.4
First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015 |
Number of individuals with the variant: 9
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Nevus sebaceous
Affected status: yes
Allele origin:
somatic
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001737088.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
|
|
|
Pathogenic
(Jul 19, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001444340.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Hepatosplenomegaly (present) , Autoimmune hemolytic anemia (present)
Sex: female
|
|
|
Pathogenic
(Aug 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
RASopathy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002117438.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 13 of the KRAS protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 13 of the KRAS protein (p.Gly13Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with oculoectodermal syndrome, as a mosaic variant (PMID: 25808193). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12580). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRAS protein function. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248878.24
First in ClinVar: May 12, 2020 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001952799.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
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: SCV001552665.2 First in ClinVar: Apr 13, 2021 Last updated: Nov 29, 2022 |
Number of individuals with the variant: 76
|
|
|
Pathogenic
(Mar 10, 2016)
|
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: SCV000504458.1
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: SCV000504459.1
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: SCV000504461.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(Oct 02, 2014)
|
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: SCV000504462.1
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: SCV000504460.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001972639.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
Pathogenic
(Jul 01, 2015)
|
no assertion criteria provided
Method: literature only
|
BREAST ADENOCARCINOMA, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000033656.6
First in ClinVar: Apr 04, 2013 Last updated: Mar 12, 2022 |
Comment on evidence:
Breast Adenocarcinoma, Somatic In a cell line from a human breast adenocarcinoma (114480), Kozma et al. (1987) identified a heterozygous G-to-A transition in exon 1 … (more)
Breast Adenocarcinoma, Somatic In a cell line from a human breast adenocarcinoma (114480), Kozma et al. (1987) identified a heterozygous G-to-A transition in exon 1 of the KRAS2 gene, resulting in a gly13-to-asp (G13D) substitution and activation of the protein. Juvenile Myelomonocytic Leukemia, Somatic In white blood cells derived from a 7-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G13D mutation in the KRAS gene. RAS-associated Autoimmune Leukoproliferative Disorder, Somatic In 2 unrelated children with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Takagi et al. (2011) identified a somatic heterozygous G13D mutation in the KRAS gene. The mutation was seen exclusively in the hematopoietic cell line, including granulocytes, monocytes, and lymphocytes. Takagi et al. (2011) noted that the same somatic mutation had been found in patients with JMML, and they postulated that the variable clinical and hematologic features of the 2 disorders may be related to the stage of differentiation at which the KRAS mutation is acquired. Oculoectodermal Syndrome In a patient (patient 1) with oculoectodermal syndrome (OES; 600268), Peacock et al. (2015) performed whole-genome shotgun sequencing to compare DNA from the patient's femur nonossifying fibroma (NOF) with DNA from her peripheral blood, and identified the G13D mutation (c.38G-A, NM_033360.3) in the KRAS gene. The mutation was confirmed by both Sanger and next-generation sequencing (allelic frequency, 32.9%). The mutation was also detectable in her hyperpigmented skin, periosteum, muscle, and humerus NOF samples (allelic frequencies, 10.3-38.8%), but not in her bone marrow or peripheral blood. (less)
|
|
|
Pathogenic
(Jul 01, 2015)
|
no assertion criteria provided
Method: literature only
|
JUVENILE MYELOMONOCYTIC LEUKEMIA, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000191994.5
First in ClinVar: Nov 22, 2014 Last updated: Mar 12, 2022 |
Comment on evidence:
Breast Adenocarcinoma, Somatic In a cell line from a human breast adenocarcinoma (114480), Kozma et al. (1987) identified a heterozygous G-to-A transition in exon 1 … (more)
Breast Adenocarcinoma, Somatic In a cell line from a human breast adenocarcinoma (114480), Kozma et al. (1987) identified a heterozygous G-to-A transition in exon 1 of the KRAS2 gene, resulting in a gly13-to-asp (G13D) substitution and activation of the protein. Juvenile Myelomonocytic Leukemia, Somatic In white blood cells derived from a 7-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G13D mutation in the KRAS gene. RAS-associated Autoimmune Leukoproliferative Disorder, Somatic In 2 unrelated children with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Takagi et al. (2011) identified a somatic heterozygous G13D mutation in the KRAS gene. The mutation was seen exclusively in the hematopoietic cell line, including granulocytes, monocytes, and lymphocytes. Takagi et al. (2011) noted that the same somatic mutation had been found in patients with JMML, and they postulated that the variable clinical and hematologic features of the 2 disorders may be related to the stage of differentiation at which the KRAS mutation is acquired. Oculoectodermal Syndrome In a patient (patient 1) with oculoectodermal syndrome (OES; 600268), Peacock et al. (2015) performed whole-genome shotgun sequencing to compare DNA from the patient's femur nonossifying fibroma (NOF) with DNA from her peripheral blood, and identified the G13D mutation (c.38G-A, NM_033360.3) in the KRAS gene. The mutation was confirmed by both Sanger and next-generation sequencing (allelic frequency, 32.9%). The mutation was also detectable in her hyperpigmented skin, periosteum, muscle, and humerus NOF samples (allelic frequencies, 10.3-38.8%), but not in her bone marrow or peripheral blood. (less)
|
|
|
Pathogenic
(Jul 01, 2015)
|
no assertion criteria provided
Method: literature only
|
RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000191995.5
First in ClinVar: Nov 22, 2014 Last updated: Mar 12, 2022 |
Comment on evidence:
Breast Adenocarcinoma, Somatic In a cell line from a human breast adenocarcinoma (114480), Kozma et al. (1987) identified a heterozygous G-to-A transition in exon 1 … (more)
Breast Adenocarcinoma, Somatic In a cell line from a human breast adenocarcinoma (114480), Kozma et al. (1987) identified a heterozygous G-to-A transition in exon 1 of the KRAS2 gene, resulting in a gly13-to-asp (G13D) substitution and activation of the protein. Juvenile Myelomonocytic Leukemia, Somatic In white blood cells derived from a 7-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G13D mutation in the KRAS gene. RAS-associated Autoimmune Leukoproliferative Disorder, Somatic In 2 unrelated children with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Takagi et al. (2011) identified a somatic heterozygous G13D mutation in the KRAS gene. The mutation was seen exclusively in the hematopoietic cell line, including granulocytes, monocytes, and lymphocytes. Takagi et al. (2011) noted that the same somatic mutation had been found in patients with JMML, and they postulated that the variable clinical and hematologic features of the 2 disorders may be related to the stage of differentiation at which the KRAS mutation is acquired. Oculoectodermal Syndrome In a patient (patient 1) with oculoectodermal syndrome (OES; 600268), Peacock et al. (2015) performed whole-genome shotgun sequencing to compare DNA from the patient's femur nonossifying fibroma (NOF) with DNA from her peripheral blood, and identified the G13D mutation (c.38G-A, NM_033360.3) in the KRAS gene. The mutation was confirmed by both Sanger and next-generation sequencing (allelic frequency, 32.9%). The mutation was also detectable in her hyperpigmented skin, periosteum, muscle, and humerus NOF samples (allelic frequencies, 10.3-38.8%), but not in her bone marrow or peripheral blood. (less)
|
|
|
Pathogenic
(Jul 01, 2015)
|
no assertion criteria provided
Method: literature only
|
OCULOECTODERMAL SYNDROME, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000930607.3
First in ClinVar: Aug 05, 2019 Last updated: Mar 12, 2022 |
Comment on evidence:
Breast Adenocarcinoma, Somatic In a cell line from a human breast adenocarcinoma (114480), Kozma et al. (1987) identified a heterozygous G-to-A transition in exon 1 … (more)
Breast Adenocarcinoma, Somatic In a cell line from a human breast adenocarcinoma (114480), Kozma et al. (1987) identified a heterozygous G-to-A transition in exon 1 of the KRAS2 gene, resulting in a gly13-to-asp (G13D) substitution and activation of the protein. Juvenile Myelomonocytic Leukemia, Somatic In white blood cells derived from a 7-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G13D mutation in the KRAS gene. RAS-associated Autoimmune Leukoproliferative Disorder, Somatic In 2 unrelated children with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Takagi et al. (2011) identified a somatic heterozygous G13D mutation in the KRAS gene. The mutation was seen exclusively in the hematopoietic cell line, including granulocytes, monocytes, and lymphocytes. Takagi et al. (2011) noted that the same somatic mutation had been found in patients with JMML, and they postulated that the variable clinical and hematologic features of the 2 disorders may be related to the stage of differentiation at which the KRAS mutation is acquired. Oculoectodermal Syndrome In a patient (patient 1) with oculoectodermal syndrome (OES; 600268), Peacock et al. (2015) performed whole-genome shotgun sequencing to compare DNA from the patient's femur nonossifying fibroma (NOF) with DNA from her peripheral blood, and identified the G13D mutation (c.38G-A, NM_033360.3) in the KRAS gene. The mutation was confirmed by both Sanger and next-generation sequencing (allelic frequency, 32.9%). The mutation was also detectable in her hyperpigmented skin, periosteum, muscle, and humerus NOF samples (allelic frequencies, 10.3-38.8%), but not in her bone marrow or peripheral blood. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Encephalocraniocutaneous lipomatosis
Affected status: unknown
Allele origin:
somatic
|
GeneReviews
Accession: SCV002099548.2
First in ClinVar: Mar 03, 2022 Last updated: Oct 01, 2022 |
|
|
|
Uncertain significance
(Dec 01, 2019)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Older and outlier claim with insufficient supporting evidence
Source: ClinGen
|
Noonan syndrome and Noonan-related syndrome
Affected status: unknown
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002060774.1
First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022 |
|
|
| click to load more click to collapse | |||||
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 13 of the KRAS protein (p.Gly13Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with oculoectodermal syndrome, as a mosaic variant (PMID: 25808193). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12580). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRAS protein function. For these reasons, this variant has been classified as Pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The KRAS c.38G>A variant is predicted to result in the amino acid substitution p.Gly13Asp. This variant has been reported as a mosaic change in two patients with RAS-associated autoimmune leukoproliferative disorder, oculoectodermal syndrome/encephalocraniocutaneous lipomatosis, and an individual with myelodysplastic/myeloproliferative disease who was also positive for additional variants (Takagi et al. 2011. PubMed ID: 21063026; Peacock et al. 2015. PubMed ID: 25808193; Moog and Moog. 2022. PubMed ID: 35099867; Patient 2, Ismael et al. 2012. PubMed ID: 22571758). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 13 of the KRAS protein (p.Gly13Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with oculoectodermal syndrome, as a mosaic variant (PMID: 25808193). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12580). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRAS protein function. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Encephalocraniocutaneous Lipomatosis. | Adam MP | - | 2022 | PMID: 35099867 |
| Cetuximab treatment for metastatic colorectal cancer with KRAS p.G13D mutations improves progression-free survival. | Osumi H | Molecular and clinical oncology | 2015 | PMID: 26623049 |
| Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations. | Peacock JD | American journal of medical genetics. Part A | 2015 | PMID: 25808193 |
| Comparative analysis of KRAS codon 12, 13, 18, 61, and 117 mutations using human MCF10A isogenic cell lines. | Stolze B | Scientific reports | 2015 | PMID: 25705018 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| KRAS mutations: variable incidences in a Brazilian cohort of 8,234 metastatic colorectal cancer patients. | Gil Ferreira C | BMC gastroenterology | 2014 | PMID: 24720724 |
| KRAS G13D Mutation and Sensitivity to Cetuximab or Panitumumab in a Colorectal Cancer Cell Line Model. | Kumar SS | Gastrointestinal cancer research : GCR | 2014 | PMID: 24558511 |
| Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. | Ho AL | The New England journal of medicine | 2013 | PMID: 23406027 |
| Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab. | Peeters M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2013 | PMID: 23182985 |
| Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. | Tejpar S | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2012 | PMID: 22734028 |
| De novo childhood myelodysplastic/myeloproliferative disease with unique molecular characteristics. | Ismael O | British journal of haematology | 2012 | PMID: 22571758 |
| 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 |
| Inhibition of MEK and PI3K/mTOR suppresses tumor growth but does not cause tumor regression in patient-derived xenografts of RAS-mutant colorectal carcinomas. | Migliardi G | Clinical cancer research : an official journal of the American Association for Cancer Research | 2012 | PMID: 22392911 |
| Epidermal growth factor receptor blockers for the treatment of ovarian cancer. | Haldar K | The Cochrane database of systematic reviews | 2011 | PMID: 21975775 |
| Effect of simvastatin on cetuximab resistance in human colorectal cancer with KRAS mutations. | Lee J | Journal of the National Cancer Institute | 2011 | PMID: 21398618 |
| 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 |
| Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation. | Takagi M | Blood | 2011 | PMID: 21063026 |
| Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. | De Roock W | JAMA | 2010 | PMID: 20978259 |
| 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 |
| 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 |
| 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 |
| 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 |
| Hyperactive Ras in developmental disorders and cancer. | Schubbert S | Nature reviews. Cancer | 2007 | PMID: 17384584 |
| Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations. | Matsuda K | Blood | 2007 | PMID: 17332249 |
| KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. | Lièvre A | Cancer research | 2006 | PMID: 16618717 |
| Implications of NRAS mutations in AML: a study of 2502 patients. | Bacher U | Blood | 2006 | PMID: 16434492 |
| Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma. | Rothenberg ML | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2005 | PMID: 16361624 |
| KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. | Pao W | PLoS medicine | 2005 | PMID: 15696205 |
| BRAF and RAS mutations in human lung cancer and melanoma. | Brose MS | Cancer research | 2002 | PMID: 12460918 |
| RAS gene mutations in childhood acute myeloid leukemia: a Pediatric Oncology Group study. | Vogelstein B | Genes, chromosomes & cancer | 1990 | PMID: 2278970 |
| ras oncogenes in human cancer: a review. | Bos JL | Cancer research | 1989 | PMID: 2547513 |
| The human c-Kirsten ras gene is activated by a novel mutation in codon 13 in the breast carcinoma cell line MDA-MB231. | Kozma SC | Nucleic acids research | 1987 | PMID: 3627975 |
| 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.38G>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. |
|---|---|---|---|---|
|
|
Oncogenic
criteria provided, single submitter
|
Jul 31, 2024 | RCV004668723.1 |
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. |
Tumor type
Help
The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
|
Oncogenic
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neoplasm
Affected status: unknown
Allele origin:
somatic
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094256.1
First In ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
|
Comment:
The KRAS c.38G>A variant is predicted to result in the amino acid substitution p.Gly13Asp. This variant has been reported as a mosaic change in two patients with RAS-associated autoimmune leukoproliferative disorder, oculoectodermal syndrome/encephalocraniocutaneous lipomatosis, and an individual with myelodysplastic/myeloproliferative disease who was also positive for additional variants (Takagi et al. 2011. PubMed ID: 21063026; Peacock et al. 2015. PubMed ID: 25808193; Moog and Moog. 2022. PubMed ID: 35099867; Patient 2, Ismael et al. 2012. PubMed ID: 22571758). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 13 of the KRAS protein (p.Gly13Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with oculoectodermal syndrome, as a mosaic variant (PMID: 25808193). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12580). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRAS protein function. For these reasons, this variant has been classified as Pathogenic.
Citations for somatic classification of this variant
Help| There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs112445441 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.