ClinVar Genomic variation as it relates to human health
NM_004985.5(KRAS):c.451-5560T>A
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.
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.
Uncertain significance(1); Benign(1); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004985.5(KRAS):c.451-5560T>A
Variation ID: 46541 Accession: VCV000046541.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p12.1 12: 25215471 (GRCh38) [ NCBI UCSC ] 12: 25368405 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 8, 2024 Aug 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004985.5:c.451-5560T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_033360.4:c.540T>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_203524.1:p.Cys180Ter nonsense NM_001369786.1:c.540T>A NP_001356715.1:p.Cys180Ter nonsense NM_001369787.1:c.451-5560T>A intron variant NC_000012.12:g.25215471A>T NC_000012.11:g.25368405A>T NG_007524.2:g.40533T>A LRG_344:g.40533T>A LRG_344t1:c.451-5560T>A LRG_344t2:c.540T>A LRG_344p2:p.Cys180Ter - Protein change
- C180*
- Other names
- p.C180*:TGT>TGA
- Canonical SPDI
- NC_000012.12:25215470:A:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00006
The Genome Aggregation Database (gnomAD) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00012
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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KRAS | No evidence available | No evidence available |
GRCh38 GRCh37 |
463 | 521 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Jul 2, 2018 | RCV000039811.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 29, 2021 | RCV001526812.2 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2024 | RCV001719761.3 |
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
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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
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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
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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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Benign
(Jul 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919562.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: KRAS c.540T>A (p.Cys180X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: KRAS c.540T>A (p.Cys180X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. However, gain-of-function is the established molecular mechanism for disease for KRAS variants associated with Noonan spectrum disorders. The variant allele was found at a frequency of 7.9e-05 in 276946 control chromosomes (gnomAD). The observed variant frequency is approximately 6-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in KRAS causing Noonan Syndrome and Related Conditions phenotype (1.3e-05), strongly suggesting that the variant is benign. The variant, c.540T>A, has been reported in the literature in an individual presenting with obesity, webbed neck, acne, bilateral inguinal hernia repair, abnormal pubertal development (Bhoj_2016) and an individual presenting with constrictive pericarditis (Herkert_2018) in whom it was classified as "Likely Benign" and "VUS" respectively. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Another ClinVar submission from a clinical diagnostic laboratory (evaluation before 2014) indicate the variant co-occurred with another pathogenic variant in a different gene and the laboratory classified the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Nov 07, 2013)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000063500.5
First in ClinVar: May 03, 2013 Last updated: May 29, 2016 |
Comment:
Cys180X in exon 5 of KRAS: This variant is not expected to have clinical signifi cance because it has been previously identified by our laboratory … (more)
Cys180X in exon 5 of KRAS: This variant is not expected to have clinical signifi cance because it has been previously identified by our laboratory in one individ ual who does not have clinical features of Noonan spectrum disorders and a secon d individual who is affected but carries a pathogenic variant in another gene wh ich is likely responsible for the disease. In addition, variants associated with Noonan spectrum disorders are typically gain-of-function; therefore, nonsense v ariants such as this are not common. Furthermore, this variant is located in an exon which is alternatively spliced in one isoform of KRAS. No pathogenic sequen ce variants in this region of the gene have been previously described. This vari ant has also been identified in 0.01% (1/8598) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP r s373169526). In summary, this variant is likely benign. (less)
Number of individuals with the variant: 4
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Likely benign
(Oct 31, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000207886.9
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 26122175, 29625052, 26689913)
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Uncertain significance
(Mar 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardio-facio-cutaneous syndrome
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV001737457.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Comment:
The KRAS c.540T>A (p.Cys180X) change is a nonsense variant in an alternate transcript of the KRAS gene that is predicted to cause protein truncation. The … (more)
The KRAS c.540T>A (p.Cys180X) change is a nonsense variant in an alternate transcript of the KRAS gene that is predicted to cause protein truncation. The disease mechanism for RASopathies is gain-of-function caused by missense changes and protein truncating variants do not have an established correlation to disease (BP1). This variant has a maximum subpopulation frequency of 0.015% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/12-25368405-A-T?dataset=gnomad_r2_1). This is neither rare or greater than expected for the disorder based on thresholds defined by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581). This variant has been reported in an individual with constrictive pericarditis (PMID: 29517769), as well as individuals who do not present with clinical features of RASopathy disorders (PMID: 27763634, internal data). Data deposited into ClinVar indicates that this variant was identified in an individual who is affected by carries a pathogenic variant in another gene which is likely responsible for the disease (ClinVar Accession: SCV000063500.5). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BP1. (less)
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Likely benign
(Aug 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV005330231.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
KRAS: BS2
Number of individuals with the variant: 1
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Toward an effective exome-based genetic testing strategy in pediatric dilated cardiomyopathy. | Herkert JC | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29517769 |
Phenotypic predictors and final diagnoses in patients referred for RASopathy testing by targeted next-generation sequencing. | Bhoj EJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27763634 |
Text-mined citations for rs373169526 ...
HelpRecord last updated Oct 08, 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.