4-54727437-T-C

Variant names:

• chr4-54727437-T-C
• rs121913235
• NM_000222.3:c.1669T>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000222.3(KIT):​c.1669T>C​(p.Trp557Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W557C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIT NM_000222.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.86
• Publications: 171 publications found

Genes affected

KIT (HGNC:6342): (KIT proto-oncogene, receptor tyrosine kinase) This gene encodes a receptor tyrosine kinase. This gene was initially identified as a homolog of the feline sarcoma viral oncogene v-kit and is often referred to as proto-oncogene c-Kit. The canonical form of this glycosylated transmembrane protein has an N-terminal extracellular region with five immunoglobulin-like domains, a transmembrane region, and an intracellular tyrosine kinase domain at the C-terminus. Upon activation by its cytokine ligand, stem cell factor (SCF), this protein phosphorylates multiple intracellular proteins that play a role in in the proliferation, differentiation, migration and apoptosis of many cell types and thereby plays an important role in hematopoiesis, stem cell maintenance, gametogenesis, melanogenesis, and in mast cell development, migration and function. This protein can be a membrane-bound or soluble protein. Mutations in this gene are associated with gastrointestinal stromal tumors, mast cell disease, acute myelogenous leukemia, and piebaldism. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2020]

KIT Gene-Disease associations (from GenCC):

• gastrointestinal stromal tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics
• piebaldism

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• cutaneous mastocytosis

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mastocytosis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 36 uncertain in NM_000222.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the KIT gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 54 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 2.5806 (below the threshold of 3.09). Trascript score misZ: 4.1549 (above the threshold of 3.09). GenCC associations: The gene is linked to cutaneous mastocytosis, gastrointestinal stromal tumor, mastocytosis, piebaldism.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 4-54727437-T-C is Pathogenic according to our data. Variant chr4-54727437-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 375909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIT	NM_000222.3	c.1669T>C	p.Trp557Arg	missense_variant	Exon 11 of 21	ENST00000288135.6	NP_000213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIT	ENST00000288135.6	c.1669T>C	p.Trp557Arg	missense_variant	Exon 11 of 21	1	NM_000222.3	ENSP00000288135.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gastrointestinal stromal tumor Pathogenic:1

Nov 28, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (ExAC no frequency). 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). 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. 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). 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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 23, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	.;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	.;M
PhyloP100		7.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-12	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.79		.;Gain of disorder (P = 0.044);
MVP		0.96
MPC		1.8
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.94
gMVP		0.93
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121913235; hg19: chr4-55593603; COSMIC: COSV55386440; COSMIC: COSV55386440;