ClinVar Genomic variation as it relates to human health
NM_000222.3(KIT):c.1669T>C (p.Trp557Arg)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000222.3(KIT):c.1669T>C (p.Trp557Arg)
Variation ID: 375909 Accession: VCV000375909.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q12 4: 54727437 (GRCh38) [ NCBI UCSC ] 4: 55593603 (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 Mar 8, 2017 Feb 20, 2024 Aug 18, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000222.3:c.1669T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000213.1:p.Trp557Arg missense NM_001093772.2:c.1657T>C NP_001087241.1:p.Trp553Arg missense NM_001385284.1:c.1672T>C NP_001372213.1:p.Trp558Arg missense NM_001385285.1:c.1669T>C NP_001372214.1:p.Trp557Arg missense NM_001385286.1:c.1657T>C NP_001372215.1:p.Trp553Arg missense NM_001385288.1:c.1660T>C NP_001372217.1:p.Trp554Arg missense NM_001385290.1:c.1672T>C NP_001372219.1:p.Trp558Arg missense NM_001385292.1:c.1660T>C NP_001372221.1:p.Trp554Arg missense NC_000004.12:g.54727437T>C NC_000004.11:g.55593603T>C NG_007456.1:g.74443T>C LRG_307:g.74443T>C LRG_307t1:c.1669T>C LRG_307p1:p.Trp557Arg - Protein change
- W557R, W553R, W554R, W558R
- Other names
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- Canonical SPDI
- NC_000004.12:54727436:T:C
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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.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
Help
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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KIT | - | - |
GRCh38 GRCh37 |
2794 | 2820 |
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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Pathogenic (1) |
no assertion criteria provided
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Oct 2, 2014 | RCV000425331.2 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Nov 28, 2019 | RCV000432558.10 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 2, 2014 | RCV000442970.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 18, 2021 | RCV002402117.2 |
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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Pathogenic
(Aug 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002706118.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.W557R pathogenic mutation (also known as c.1669T>C), located in coding exon 11 of the KIT gene, results from a T to C substitution at … (more)
The p.W557R pathogenic mutation (also known as c.1669T>C), located in coding exon 11 of the KIT gene, results from a T to C substitution at nucleotide position 1669. The tryptophan at codon 557 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been observed in multiple individuals with a personal history that is consistent with KIT-related disease and this variant has been shown to segregate in affected individuals in multiple families (Ambry internal data; Hirota S et al. Am J Surg Pathol, 2000 Feb;24:326-7; Antonescu CR et al. Clin Cancer Res, 2003 Aug;9:3329-37; Robson ME et al. Clin Cancer Res, 2004 Feb;10:1250-4; Farag S et al. Fam Cancer, 2018 04;17:247-253). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Nov 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Gastrointestinal stromal tumor
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000630433.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. While functional studies have not been reported for this p.Trp557Arg variant, the tryptophan residue is located in the KIT juxtamembrane domain, which is required for KIT autoinhibition (PMID: 16226710, 12697809).  A different substitution at this codon, p.Trp557Ala, was shown to result in loss of phosphorylation inhibition and gain-of-function of the KIT protein (PMID: 10224103). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported to segregate with multiple gastrointestinal stromal tumors (GIST), hyperpigmentation and dysphagia in one family (PMID: 14977822), and with GIST in another family (PMID: 10680913). ClinVar contains an entry for this variant (Variation ID: 375909). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with arginine at codon 557 of the KIT protein (p.Trp557Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. (less)
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Pathogenic
(Oct 02, 2014)
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no assertion criteria provided
Method: literature only
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Melanoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504168.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Pathogenic
(Oct 02, 2014)
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no assertion criteria provided
Method: literature only
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Thymoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504169.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(Jul 14, 2015)
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no assertion criteria provided
Method: literature only
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Gastrointestinal stromal tumor
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504170.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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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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Remarkable effects of imatinib in a family with young onset gastrointestinal stromal tumors and cutaneous hyperpigmentation associated with a germline KIT-Trp557Arg mutation: case report and literature overview. | Farag S | Familial cancer | 2018 | PMID: 28710566 |
Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
Activating c-KIT mutations in a subset of thymic carcinoma and response to different c-KIT inhibitors. | Schirosi L | Annals of oncology : official journal of the European Society for Medical Oncology | 2012 | PMID: 22357254 |
Sunitinib therapy for melanoma patients with KIT mutations. | Minor DR | Clinical cancer research : an official journal of the American Association for Cancer Research | 2012 | PMID: 22261812 |
Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. | Guo J | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21690468 |
KIT as a therapeutic target in metastatic melanoma. | Carvajal RD | JAMA | 2011 | PMID: 21642685 |
Response to imatinib mesylate depends on the presence of the V559A-mutated KIT oncogene. | Terheyden P | The Journal of investigative dermatology | 2010 | PMID: 19812602 |
Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates. | Woodman SE | Molecular cancer therapeutics | 2009 | PMID: 19671763 |
KIT gene mutations and copy number in melanoma subtypes. | Beadling C | Clinical cancer research : an official journal of the American Association for Cancer Research | 2008 | PMID: 18980976 |
Complete response of stage IV anal mucosal melanoma expressing KIT Val560Asp to the multikinase inhibitor sorafenib. | Quintás-Cardama A | Nature clinical practice. Oncology | 2008 | PMID: 18936790 |
Dose-dependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation. | Lutzky J | Pigment cell & melanoma research | 2008 | PMID: 18510589 |
Major response to imatinib mesylate in KIT-mutated melanoma. | Hodi FS | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2008 | PMID: 18421059 |
L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition. | Antonescu CR | International journal of cancer | 2007 | PMID: 17372901 |
Structure and regulation of Kit protein-tyrosine kinase--the stem cell factor receptor. | Roskoski R Jr | Biochemical and biophysical research communications | 2005 | PMID: 16226710 |
Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412. | Growney JD | Blood | 2005 | PMID: 15790786 |
Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia. | Robson ME | Clinical cancer research : an official journal of the American Association for Cancer Research | 2004 | PMID: 14977822 |
Association of KIT exon 9 mutations with nongastric primary site and aggressive behavior: KIT mutation analysis and clinical correlates of 120 gastrointestinal stromal tumors. | Antonescu CR | Clinical cancer research : an official journal of the American Association for Cancer Research | 2003 | PMID: 12960119 |
Gain-of-function mutation at the extracellular domain of KIT in gastrointestinal stromal tumours. | Hirota S | The Journal of pathology | 2001 | PMID: 11276010 |
Cause of familial and multiple gastrointestinal autonomic nerve tumors with hyperplasia of interstitial cells of Cajal is germline mutation of the c-kit gene. | Hirota S | The American journal of surgical pathology | 2000 | PMID: 10680913 |
Inhibition of spontaneous receptor phosphorylation by residues in a putative alpha-helix in the KIT intracellular juxtamembrane region. | Ma Y | The Journal of biological chemistry | 1999 | PMID: 10224103 |
Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. | Hirota S | Science (New York, N.Y.) | 1998 | PMID: 9438854 |
Constitutively activating mutations of c-kit receptor tyrosine kinase confer factor-independent growth and tumorigenicity of factor-dependent hematopoietic cell lines. | Kitayama H | Blood | 1995 | PMID: 7530509 |
http://docm.genome.wustl.edu/variants/ENST00000288135:c.1669T>C | - | - | - | - |
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Text-mined citations for rs121913235 ...
HelpRecord last updated Apr 15, 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.