rs121913521

Positions:

• chr4-54727447-T-A
• chr4-54727447-T-C
• chr4-54727447-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000222.3(KIT):​c.1679T>A​(p.Val560Asp) 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V560E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIT NM_000222.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 7.86

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.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_000222.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-54727447-TT-AA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376735.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIT. . Gene score misZ 2.5806 (greater than the threshold 3.09). Trascript score misZ 4.1549 (greater than threshold 3.09). GenCC has associacion of gene with piebaldism, gastrointestinal stromal tumor, mastocytosis, cutaneous mastocytosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 4-54727447-T-A is Pathogenic according to our data. Variant chr4-54727447-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375914.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIT	NM_000222.3	c.1679T>A	p.Val560Asp	missense_variant	11/21	ENST00000288135.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIT	ENST00000288135.6	c.1679T>A	p.Val560Asp	missense_variant	11/21	1	NM_000222.3	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gastrointestinal stromal tumor Pathogenic:1 Other:1

-, no assertion criteria provided	research	National Institute of Cancer Research, National Health Research Institutes	-	the literature -
Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	May 13, 2016	- -

Melanoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2024

The p.V560D variant (also known as c.1679T>A), located in coding exon 11 of the KIT gene, results from a T to A substitution at nucleotide position 1679. The valine at codon 560 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variant has been observed in at least one individual with a personal and/or family history that is consistent with KIT-related gastrointestinal stromal tumor syndrome (Ambry internal data). Protein functional studies have shown this amino acid to be critical (Ma Y et al. J Biol Chem, 1999 May;274:13399-402). This variant has been identified as a common somatic alteration in gastrointestinal stromal tumors (Taniguchi M et al. Cancer Res, 1999 Sep;59:4297-300; Tarn C et al. Clin Cancer Res, 2005 May;11:3668-77; Gomes AL et al. Am J Clin Pathol, 2007 Jan;127:89-96; Steigen SE et al. APMIS, 2007 Apr;115:289-98; Tokunaga M et al. Intern Med, 2018 Jun;57:1719-1723). Close match alterations (p.V560del, p.V560G) have been observed as germline variants that segregate with disease in patients with gastrointestinal stromal tumors (Kang DY et al. Am J Surg Pathol, 2007 Feb;31:224-32; Bamba S et al. Intern Med, 2015 Apr;54:759-64). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	.;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.3	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.69		.;Gain of ubiquitination at K558 (P = 0.0477);
MVP		0.89
MPC		1.7
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.95
gMVP		0.88

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: rs121913521; hg19: chr4-55593613; COSMIC: COSV55386785; COSMIC: COSV55386785;