NM_000222.3(KIT):c.2485G>C (p.Ala829Pro) AND Gastrointestinal stromal tumor

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jan 5, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000428554.4

Allele description [Variation Report for NM_000222.3(KIT):c.2485G>C (p.Ala829Pro)]

NM_000222.3(KIT):c.2485G>C (p.Ala829Pro)

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.2485G>C (p.Ala829Pro)

HGVS:

NC_000004.12:g.54736498G>C
NG_007456.1:g.83504G>C
NM_000222.3:c.2485G>CMANE SELECT
NM_001093772.2:c.2473G>C
NM_001385284.1:c.2488G>C
NM_001385285.1:c.2482G>C
NM_001385286.1:c.2470G>C
NM_001385288.1:c.2476G>C
NM_001385290.1:c.2485G>C
NM_001385292.1:c.2473G>C
NP_000213.1:p.Ala829Pro
NP_001087241.1:p.Ala825Pro
NP_001372213.1:p.Ala830Pro
NP_001372214.1:p.Ala828Pro
NP_001372215.1:p.Ala824Pro
NP_001372217.1:p.Ala826Pro
NP_001372219.1:p.Ala829Pro
NP_001372221.1:p.Ala825Pro
LRG_307:g.83504G>C
NC_000004.11:g.55602664G>C

Protein change:

A824P

Links:

dbSNP: rs1057519713

NCBI 1000 Genomes Browser:

rs1057519713

Molecular consequence:

NM_000222.3:c.2485G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001093772.2:c.2473G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001385284.1:c.2488G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001385285.1:c.2482G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001385286.1:c.2470G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001385288.1:c.2476G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001385290.1:c.2485G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001385292.1:c.2473G>C - 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
SCV000504224	Database of Curated Mutations (DoCM)	no assertion criteria provided	Likely pathogenic (Dec 26, 2014)	somatic	literature only	PubMed (3) [See all records that cite these PMIDs] 23582185, 21689725, 17259998 Citation Link,
SCV004551573	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 5, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29923175, 31497890, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000504224

Database of Curated Mutations (DoCM)

no assertion criteria provided

Likely pathogenic
(Dec 26, 2014)

somatic

literature only

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV004551573

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 5, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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	somatic	yes	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Secondary c-Kit mutations confer acquired resistance to RTK inhibitors in c-Kit mutant melanoma cells.

Todd JR, Becker TM, Kefford RF, Rizos H.

Pigment Cell Melanoma Res. 2013 Jul;26(4):518-26. doi: 10.1111/pcmr.12107. Epub 2013 May 13.

PubMed [citation]

PMID:: 23582185

Novel, activating KIT-N822I mutation in familial cutaneous mastocytosis.

Wasag B, Niedoszytko M, Piskorz A, Lange M, Renke J, Jassem E, Biernat W, Debiec-Rychter M, Limon J.

Exp Hematol. 2011 Aug;39(8):859-65.e2. doi: 10.1016/j.exphem.2011.05.009. Epub 2011 May 27.

PubMed [citation]

PMID:: 21689725

See all PubMed Citations (6)

Details of each submission

From Database of Curated Mutations (DoCM), SCV000504224.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004551573.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

ClinVar contains an entry for this variant (Variation ID: 375933). 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. 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. This missense change has been observed in individual(s) with gastrointestinal stromal tumor syndrome and/or hyperpigmentation and lentigines (PMID: 29923175, 31497890; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 829 of the KIT protein (p.Ala829Pro).

#	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

Last Updated: Sep 29, 2024

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