VCV000177881.31 - ClinVar

NM_004985.5(KRAS):c.183A>C (p.Gln61His)

Germline

Classification

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

(8)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

Clinical impact

The aggregate somatic clinical impact for this variant for one or more tumor types, using the AMP/ASCO/CAP terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate somatic clinical impact 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.

Tier II (Potential) for Primary intracranial sarcoma, DICER1-mutant

criteria provided, single submitter

Somatic

Oncogenicity

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

(1)

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

Oncogenic

criteria provided, single submitter

Variant Details

Identifiers

NM_004985.5(KRAS):c.183A>C (p.Gln61His)

Variation ID: 177881 Accession: VCV000177881.31

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p12.1 12: 25227341 (GRCh38) [ NCBI UCSC ] 12: 25380275 (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	May 29, 2016	Oct 20, 2024	Oct 10, 2022
Somatic - Clinical impact	Sep 1, 2024	Sep 1, 2024	Jul 31, 2024
Somatic - Oncogenicity	Aug 11, 2024	Aug 11, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004985.5:c.183A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004976.2:p.Gln61His	missense
NM_033360.4:c.183A>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_203524.1:p.Gln61His	missense
NM_001369786.1:c.183A>C	NP_001356715.1:p.Gln61His	missense
NM_001369787.1:c.183A>C	NP_001356716.1:p.Gln61His	missense
NC_000012.12:g.25227341T>G
NC_000012.11:g.25380275T>G
NG_007524.2:g.28663A>C
LRG_344:g.28663A>C
LRG_344t1:c.183A>C	LRG_344p1:p.Gln61His
LRG_344t2:c.183A>C	LRG_344p2:p.Gln61His
	P01116:p.Gln61His

... more HGVS ... less HGVS

Protein change

Q61H

Other names

Canonical SPDI

NC_000012.12:25227340:T:G

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

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

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

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA180922 UniProtKB: P01116#VAR_006841 dbSNP: rs17851045 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
KRAS		No evidence available	No evidence available	GRCh38 GRCh37	465	523

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.
Non-small cell lung carcinoma	Pathogenic (2)	no assertion criteria provided	Oct 2, 2014	RCV000154530.7
Acute myeloid leukemia	Likely pathogenic (1)	no assertion criteria provided	Oct 2, 2014	RCV000424748.2
Neoplasm of the large intestine	Pathogenic (1)	no assertion criteria provided	Jul 14, 2015	RCV000444370.2
Juvenile myelomonocytic leukemia	Likely pathogenic (1)	no assertion criteria provided	-	RCV001004043.2
not provided	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2022	RCV002056053.18
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Nov 10, 2020	RCV002408686.3
RASopathy	Uncertain significance (1)	criteria provided, single submitter	Oct 10, 2022	RCV002514970.4

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.
Uncertain significance (Nov 10, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002710946.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The p.Q61H variant (also known as c.183A>C), located in coding exon 2 of the KRAS gene, results from an A to C substitution at nucleotide … (more) The p.Q61H variant (also known as c.183A>C), located in coding exon 2 of the KRAS gene, results from an A to C substitution at nucleotide position 183. The glutamine at codon 61 is replaced by histidine, an amino acid with highly similar properties. Somatic mutations impacting codon 61 of the KRAS gene are frequently observed in multiple cancer types; the p.Q61H variant is often identified in colorectal and lung adenocarcinomas as well as hematopoetic/lymphatic neoplasms (Prior IA et al. Cancer Res 2012;72(10):2457-67). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Oct 10, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RASopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002965319.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Comment: In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more) In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 177881). 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. This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 61 of the KRAS protein (p.Gln61His). (less)
Pathogenic (Jan 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002497209.18 First in ClinVar: Apr 08, 2022 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Aug 28, 2014)	no assertion criteria provided Method: clinical testing	Non-small cell lung carcinoma Affected status: not provided Allele origin: somatic	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000204202.2 First in ClinVar: Jan 31, 2015 Last updated: May 29, 2016	Publications: PubMed (1) PubMed: 15696205 Comment: proposed classification - variant undergoing re-assessment, contact laboratory Number of individuals with the variant: 7
Pathogenic (Jul 14, 2015)	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: SCV000504440.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (11) PubMed: 16361624‚ 18316791‚ 19114683‚ 19679400‚ 21228335‚ 20921462‚ 23325582‚ 16618717‚ 22722830‚ 20921465‚ 25157968 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000256078:c.183A>C
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: SCV000504441.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (5) PubMed: 16434492‚ 22407852‚ 19075190‚ 2278970‚ 3122217 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000256078:c.183A>C
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: SCV000504442.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (2) PubMed: 12460918‚ 18794081 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000256078:c.183A>C
Likely pathogenic (-)	no assertion criteria provided Method: research	Juvenile myelomonocytic leukemia Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001162253.1 First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020	Publications: PubMed (1) PubMed: 32581362 Number of individuals with the variant: 1 Sex: male

Comment:

This variant is not present in population databases (gnomAD no frequency) and it is reported in Clinvar as conflicting of pathogenicity. This missense change has been observed as a somatic variant in an individual with Dicer1-sarcoma. SIFT Algorithms suggests that this variant is likely to be deleterius. OncoKB database reported this variant as: Oncogenic, Gain-of-function with FDA levels that makes the variant as Tier IIC

Comment:

The p.Q61H variant (also known as c.183A>C), located in coding exon 2 of the KRAS gene, results from an A to C substitution at nucleotide position 183. The glutamine at codon 61 is replaced by histidine, an amino acid with highly similar properties. Somatic mutations impacting codon 61 of the KRAS gene are frequently observed in multiple cancer types; the p.Q61H variant is often identified in colorectal and lung adenocarcinomas as well as hematopoetic/lymphatic neoplasms (Prior IA et al. Cancer Res 2012;72(10):2457-67). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 177881). 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. This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 61 of the KRAS protein (p.Gln61His).

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Whole-genome sequencing of patients with rare diseases in a national health system.	Turro E	Nature	2020	PMID: 32581362
Prospective enterprise-level molecular genotyping of a cohort of cancer patients.	MacConaill LE	The Journal of molecular diagnostics : JMD	2014	PMID: 25157968
Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer.	Peeters M	Clinical cancer research : an official journal of the American Association for Cancer Research	2013	PMID: 23325582
Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer.	Misale S	Nature	2012	PMID: 22722830
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
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
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
Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer.	Neumann J	Pathology, research and practice	2009	PMID: 19679400
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
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
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 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.183A>C	-	-	-	-
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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.
Primary intracranial sarcoma, DICER1-mutant	Tier II (Potential) - diagnostic - supports diagnosis (1)		Jul 31, 2024	RCV004698422.1
Neoplasm		Oncogenic criteria provided, single submitter	Jul 31, 2024	RCV004668811.1

Submissions - Somatic

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

Tier II (Potential) - Diagnostic -
supports diagnosis

(Jul 31, 2024)

(AMP/ASCO/CAP Guidelines, 2017)

Method: clinical testing

Primary intracranial sarcoma, DICER1-mutant

Affected status: unknown

Allele origin: somatic

Molecular Pathology Unit, Bambino Gesu' Children's Hospital, IRCCS

Accession: SCV005200117.1
First In ClinVar: Sep 01, 2024
Last updated: Sep 01, 2024

Comment:

This variant is not present in population databases (gnomAD no frequency) and it is reported in Clinvar as conflicting of pathogenicity. This missense change has … (more)

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

Oncogenic

(Jul 31, 2024)

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

Method: clinical testing

Neoplasm

Affected status: unknown

Allele origin: somatic

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Accession: SCV005094251.1
First In ClinVar: Aug 11, 2024
Last updated: Aug 11, 2024

Comment:

Citations for somatic classification of this variant

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

Text-mined citations for rs17851045 ...

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

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_004985.5(KRAS):c.183A>C (p.Gln61His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Conditions - Somatic

Submissions - Somatic

Citations for somatic classification of this variant

Text-mined citations for rs17851045 ...