rs1060502543

Positions:

• chr4-54727500-TATG-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_000222.3(KIT):​c.1735_1737del​(p.Asp579del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIT NM_000222.3 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.14

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000222.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 4-54727500-TATG-T is Pathogenic according to our data. Variant chr4-54727500-TATG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 409725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIT	NM_000222.3	c.1735_1737del	p.Asp579del	inframe_deletion	11/21	ENST00000288135.6	NP_000213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIT	ENST00000288135.6	c.1735_1737del	p.Asp579del	inframe_deletion	11/21	1	NM_000222.3	ENSP00000288135	P4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gastrointestinal stromal tumor Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 09, 2023	This variant, c.1735_1737del, results in the deletion of 1 amino acid(s) of the KIT protein (p.Asp579del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with gastrointestinal stromal tumors (GIST) (PMID: 15897563, 17001171, 17943734, 25504284; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as 1756_1758delGAT and 1753del3. ClinVar contains an entry for this variant (Variation ID: 409725). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects KIT function (PMID: 9797363). For these reasons, this variant has been classified as Pathogenic. -
-, no assertion criteria provided	research	National Institute of Cancer Research, National Health Research Institutes	-	clinical data -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 09, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of one amino acid in a non-repeat region; Published functional studies suggest a damaging effect: in vitro and in vivo assays showed that the variant protein caused constitutive phosphorylation and strong kinase activity, supporting a gain-of-function effect (Nakahara et al., 1998); In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in individuals with gastrointestinal stromal tumors referred for genetic testing at GeneDx and in published literature (Tarn et al., 2005; Lasota et al., 2007; Jones et al., 2015; Wali et al., 2019); This variant is associated with the following publications: (PMID: 30280421, 28236058, 25504284, 17001171, 29568401, 27687311, 24419427, 31124195, 15897563, 9797363) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2021

The c.1735_1737delGAT pathogenic mutation (also known as p.D579del) is located in coding exon 11 of the KIT gene. This pathogenic mutation results from an in-frame GAT deletion at nucleotide positions 1735 to 1737. This results in the in-frame deletion of an aspartic acid at codon 579. This mutation has been reported as germline in multiple individuals with personal and family histories of gastrointestinal stromal tumors (GISTs), including three kindreds where this variant segregated with GIST tumors (Jones DH et al. Cancer Control, 2015 Jan;22:102-8; Lasota J et al. Am J Surg Pathol, 2006 Oct;30:1342; Wali GN et al. Clin Exp Dermatol, 2019 Jun;44:418-421; Tarn C et al. Clin Cancer Res, 2005 May;11:3668-77; Kleinbaum EP et al. Int J Cancer, 2008 Feb;122:711-8; Ambry internal data). One functional study showed consistent results between in vitro and in vivo assays that the KIT579del is an an activating gain of function alteration resulting in autophosphorylation, cell proliferation, and tumor formation in mice (Nakahara M et al. Gastroenterology, 1998 Nov;115:1090-5). Of note, this mutation is also designated as 1753del3, 1756_1758delGAT, Del579, and "deletion at codon 579 (Asp)" in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060502543; hg19: chr4-55593666;