Classification rationale

PM2 BP4 VUS

KIT c.148G>T

The KIT c.148G>T (p.Val50Leu) variant has been reported in ClinVar with predominantly uncertain significance submissions, with additional likely benign and benign submissions and no expert-panel consensus.¹ This variant is present in population databases at low frequency, measuring 0.00779% in gnomAD v2.1 and 0.00539% in gnomAD v4.1, which is below the 0.1% non-VCEP PM2 threshold and below benign stand-alone or strong frequency thresholds.² Computational evidence favors little or no impact, with SpliceAI predicting no significant splice effect (maximum delta score 0.01), a low REVEL score of 0.125, and a BayesDel score of -0.628781.³

PM2 + BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗revelbayesdel

Gene diagram · NM_000222.2 · variants mapped to exon structure

KIT NM_000222.2

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.39015e-05; MAF= 0.00539%, 87/1614054 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 9.37295e-05; MAF= 0.00937%, 6/64014 alleles, homozygotes = 0); grpmax FAF= 5.463e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 7.78772e-05; MAF= 0.00779%, 22/282496 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000147454; MAF= 0.01475%, 19/128854 alleles, homozygotes = 0); grpmax FAF= 0.00049825.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0054% · 87 / 1,614,054
0 hom · FAF 0.0055%

European (Finnish) 6 / 64,014	0.0094%
European (non-Finnish) 79 / 1,180,042	0.0067%
Remaining individuals 1 / 62,488	0.0016%
African/African American 1 / 74,936	0.0013%

+ 6 not observed (Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0078% · 22 / 282,496
0 hom · FAF 0.05%

European (non-Finnish) 19 / 128,854	0.015%
Remaining individuals 1 / 7,210	0.014%
European (Finnish) 2 / 25,122	0.008%

+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 409722)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.125. BayesDel score = -0.628781.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KIT, a receptor tyrosine kinase, is recurrently mutated in gastrointestinal stromal tumors.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105160851, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 10 PMIDs not cited in assessment

22138009 ↗ NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology. CLINVAR

23852704 ↗ Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

20963938 ↗ CEBPA-Associated Familial Acute Myeloid Leukemia (AML). CLINVAR

23970018 ↗ Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

32171751 ↗ Acute myeloid leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. CLINVAR

33226740 ↗ PMID:33226740 CLINVAR

22685257 ↗ The UK NEQAS for Molecular Genetics scheme for gastrointestinal stromal tumour: findings and recommendations following four rounds of circulation. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR