NM_000222.3(KIT):c.1900C>T (p.Arg634Trp) AND Gastrointestinal stromal tumor

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 31, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000459314.11

Allele description [Variation Report for NM_000222.3(KIT):c.1900C>T (p.Arg634Trp)]

NM_000222.3(KIT):c.1900C>T (p.Arg634Trp)

Gene:

KIT:KIT proto-oncogene, receptor tyrosine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q12

Genomic location:

Preferred name:

NM_000222.3(KIT):c.1900C>T (p.Arg634Trp)

HGVS:

NC_000004.12:g.54728031C>T
NG_007456.1:g.75037C>T
NM_000222.3:c.1900C>TMANE SELECT
NM_001093772.2:c.1888C>T
NM_001385284.1:c.1903C>T
NM_001385285.1:c.1900C>T
NM_001385286.1:c.1888C>T
NM_001385288.1:c.1891C>T
NM_001385290.1:c.1903C>T
NM_001385292.1:c.1891C>T
NP_000213.1:p.Arg634Trp
NP_000213.1:p.Arg634Trp
NP_001087241.1:p.Arg630Trp
NP_001372213.1:p.Arg635Trp
NP_001372214.1:p.Arg634Trp
NP_001372215.1:p.Arg630Trp
NP_001372217.1:p.Arg631Trp
NP_001372219.1:p.Arg635Trp
NP_001372221.1:p.Arg631Trp
LRG_307t1:c.1900C>T
LRG_307:g.75037C>T
LRG_307p1:p.Arg634Trp
NC_000004.11:g.55594197C>T
NM_000222.2:c.1900C>T

Protein change:

R630W

Links:

dbSNP: rs144369407

NCBI 1000 Genomes Browser:

rs144369407

Molecular consequence:

NM_000222.3:c.1900C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001093772.2:c.1888C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385284.1:c.1903C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385285.1:c.1900C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385286.1:c.1888C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385288.1:c.1891C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385290.1:c.1903C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001385292.1:c.1891C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Gastrointestinal stromal tumor
Synonyms:: Gastrointestinal Stromal Sarcoma; Gastrointestinal stromal tumor, somatic; Gastrointestinal stroma tumor
Identifiers:: MONDO: MONDO:0011719; MeSH: D046152; MedGen: C0238198; Orphanet: 44890; OMIM: 606764; Human Phenotype Ontology: HP:0100723

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000550069	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 31, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 25243845, 28327988, 28520972, 35753512, 15790786, 28492532
SCV004190378	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 23, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000550069

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 31, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV004190378

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 23, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel R634W c-kit mutation identified in familial mastocytosis.

Pollard WL, Beachkofsky TM, Kobayashi TT.

Pediatr Dermatol. 2015 Mar-Apr;32(2):267-70. doi: 10.1111/pde.12381. Epub 2014 Sep 22.

PubMed [citation]

PMID:: 25243845

Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial.

Guo J, Carvajal RD, Dummer R, Hauschild A, Daud A, Bastian BC, Markovic SN, Queirolo P, Arance A, Berking C, Camargo V, Herchenhorn D, Petrella TM, Schadendorf D, Sharfman W, Testori A, Novick S, Hertle S, Nourry C, Chen Q, Hodi FS.

Ann Oncol. 2017 Jun 1;28(6):1380-1387. doi: 10.1093/annonc/mdx079.

PubMed [citation]

PMID:: 28327988
PMCID:: PMC5452069

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000550069.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 634 of the KIT protein (p.Arg634Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with chronic myelomonocytic leukemia, familial mastocytosis, systemic mastocytosis and/or acral melanoma (PMID: 15790786, 25243845, 28327988, 28520972, 35753512). ClinVar contains an entry for this variant (Variation ID: 409732). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KIT function (PMID: 15790786). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004190378.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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