KIT c.2009C>T, p.Thr670Ile

Reasoning

Multiple independent, variant-specific functional studies support a damaging effect of KIT p.(Thr670Ile). In COS1-cell assays, T670I remained phosphorylated and insensitive to imatinib across 0, 1, 3, and 6 µM, including in an activating KIT background (PMID:16751810). In progressive GISTs and engineered Ba/F3 models, KIT-T670I remained phosphorylated and resistant to imatinib up to 5 µM, while PKC412 inhibited the mutant (PMID:15685537). Independent engineered-KIT assays measured strong imatinib resistance with an IC50 of 10 µM (PMID:16954519). Recombinant kinase assays using three independent experiments showed altered kinetics and higher catalytic efficiency than wild type (PMID:27527414). Orthogonal kinase, cellular signaling, and Ba/F3 proliferation assays also demonstrated T670I activity and drug-resistant signaling, with sorafenib inhibiting autophosphorylation at an IC50 of 60 nM and reducing downstream signaling (PMID:17545544). The evidence is variant-specific, includes wild-type or treatment-response comparisons and multiple assay systems, and is concordant across independent studies; it supports PS3 at strong strength, although these are research assays rather than validated clinical diagnostic-laboratory assays.

Rule

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

Evidence considered

• Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients: COS1 cells expressing KIT T670I remained phosphorylated and insensitive to imatinib at 0, 1, 3, and 6 µM; the paper reports the variant as an acquired secondary mutation.
• Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants: KIT-T670I was found in 3 of 26 progressive GISTs; KIT autophosphorylation was not inhibited by imatinib up to 5 µM, while PKC412 inhibited the mutant.
• Molecular correlates of imatinib resistance in gastrointestinal stromal tumors: engineered KIT T670I caused strong imatinib resistance with an IC50 of 10 µM, alone or with KIT V560D.
• The human tyrosine kinase Kit and its gatekeeper mutant T670I, show different kinetic properties: recombinant kinase assays in three independent experiments showed approximately twofold higher peptide and sevenfold higher ATP substrate-binding efficiencies and higher catalytic efficiency than wild type.
• Sorafenib inhibits imatinib-resistant KIT and platelet-derived growth factor receptor beta gatekeeper mutants: KIT T670I autophosphorylation was inhibited by sorafenib with an IC50 of 60 nM; cellular phosphorylation, downstream SHC/MAPK signaling, and oncogenic Ba/F3 proliferation were also inhibited.

Still missing

• The studies are research assays rather than reproducible clinical diagnostic-laboratory validation studies.

Sources

Reasoning

KIT p.Thr670Ile affects the T670 gatekeeper residue in the kinase ATP-binding pocket. Variant-specific studies identify T670 as part of the imatinib/ATP-binding pocket and demonstrate altered binding, catalytic efficiency, and kinase behavior. The exact variant is extremely rare in gnomAD v4.1 (AF 1.85916e-06; 3/1,613,636 alleles; maximum group AF 5.53e-06), with no benign classification in the supplied evidence. This supports location in a critical, well-established functional domain without evidence of benign variation.

Rule

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

Evidence considered

• Tamborini et al. 2006 describes T670I as remodeling the ATP-binding pocket, loss of the hydrogen bond between imatinib and residue T670, and reduced imatinib binding.
• Heinrich et al. 2006 reports T670I as a KIT ATP-binding-pocket mutation and shows strong imatinib resistance in engineered KIT constructs.
• Kissova et al. 2016 reports altered substrate-binding mechanism and higher catalytic efficiency for recombinant KIT T670I compared with wild type.
• gnomAD v4.1 reports the exact variant at AF 1.85916e-06, 3/1,613,636 alleles, with no homozygotes and maximum group AF 5.53e-06.

Sources

Reasoning

PM2 is met at supporting strength. gnomAD v4.1 reports the variant at AF=1.8591553485420504e-06 (3/1,613,636 alleles) with no homozygotes and grpmax FAF=5.53e-06. This is below the generic ClinGen SVI supporting threshold of <=0.0001. The gnomAD v2.1 record is concordant, with AF=7.0808992742078246e-06 from 2/282,450 alleles and no homozygotes. No governing VCEP requires a non-cancer or exome-only source, so the all-comers gnomAD v4.1 and v2.1 records are the applicable defaults.

Rule

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.

Evidence considered

• gnomAD v4.1 variant record for KIT NM_000222.3:c.2009C>T: AF=1.8591553485420504e-06 from 3/1,613,636 alleles, homozygotes=0, grpmax FAF=5.53e-06.
• gnomAD v2.1 variant record: AF=7.0808992742078246e-06 from 2/282,450 alleles, homozygotes=0; the highest observed Finnish subpopulation AF was 3.982477100756671e-05 from 1/25,110 alleles.
• Generic ClinGen-SVI calibration supplied for this case: PM2 supporting threshold <=0.0001, attributed in the prompt to ClinGen SVI 2020 and ACMG/AMP 2015 (PMID:25741868).

Sources

Reasoning

The variant is a missense substitution, NM_000222.3:c.2009C>T (p.Thr670Ile), so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for PP3 in this situation. The REVEL score is 0.895, meeting the supplied PP3 moderate threshold of >= 0.773 but not the strong threshold of >= 0.932. This satisfies PP3 at moderate strength.

Rule

PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant. ... PP3 (moderate): >= 0.773 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)

Evidence considered

• The case summary identifies NM_000222.3:c.2009C>T as the missense variant p.(Thr670Ile), so REVEL is the applicable computational path and SpliceAI is not counted for PP3.
• Local REVEL predictor lookup (source_registry key revel) reports a REVEL score of 0.895.
• The supplied ClinGen SVI REVEL calibration assigns PP3 moderate at >= 0.773 and PP3 strong at >= 0.932; the score 0.895 therefore supports PP3 at moderate strength. The calibration is Pejaver et al. 2022, PMID:36413997.

Sources

Reasoning

The variant is KIT p.Thr670Ile (T670I) and is explicitly reported in multiple studies, but the available evidence describes acquired somatic GIST resistance and functional effects, while ClinVar classifies the exact variant as uncertain significance. No previously established pathogenic variant with the same amino-acid change was identified, so the PS1 requirement is not met.

Rule

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

Evidence considered

• ClinVar exact variant NM_000222.3(KIT):c.2009C>T (p.Thr670Ile), variation 376058, is classified as uncertain significance with two clinical-laboratory submissions and no expert-panel submission.
• Debiec-Rychter et al. 2005 reports KIT-T670I in 3 of 26 progressive GISTs as an acquired secondary resistance mutation; this is not an established pathogenic germline classification.
• The available variant-specific papers report T670I functional effects and resistance, but do not establish the exact variant as a pathogenic germline variant for PS1 purposes.

Sources

Reasoning

The available literature reports KIT p.Thr670Ile itself, not a different missense substitution at residue 670 that has been established as pathogenic. The supplied PM5 candidate artifact contains no confirmed same-residue comparator, so the required different-pathogenic-missense evidence is absent.

Rule

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Evidence considered

• The reviewed variant-specific studies report KIT T670I, the same observed missense change, rather than a different missense substitution at residue 670.
• The PM5 candidate collection reports zero same-residue candidates and does not provide a confirmed pathogenic comparator.

Sources

Reasoning

The governing rule requires a reputable source to recently report the exact variant as pathogenic when the evidence is unavailable for independent evaluation. ClinVar variation 376058 has two exact-variant clinical-laboratory submissions, both Uncertain significance, with zero expert-panel submissions. The literature-pass PP5 lead PMID:25394175 is a general cancer-predisposition referral guideline and does not report this exact variant as pathogenic. No exact-variant reputable pathogenic report meeting PP5 is present.

Rule

Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.

Evidence considered

• ClinVar variation 376058 exactly matches NM_000222.3:c.2009C>T (p.Thr670Ile); both submissions are Uncertain significance, review status single submitter, and expert-panel submissions = 0.
• The literature-pass PP5 lead PMID:25394175 is a general referral guideline, not an exact-variant pathogenic classification.

Sources

Reasoning

BA1 is not met. Under the generic ACMG/AMP threshold, the allele frequency must be at least 0.05. gnomAD v4.1 reports 3/1,613,636 alleles (AF 1.8591553485420504e-06) with grpmax FAF=5.53e-06, far below 0.05. The highest observed subpopulation point estimate is 3.3333333333333335e-05 in Admixed American individuals (2/60,000 alleles), also far below the threshold; no small-isolate popmax artifact supports BA1. The variant is reported in ClinVar as uncertain significance, so there is no pathogenic consensus conflict requiring BA1 to be withheld for that reason.

Rule

Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.

Evidence considered

• gnomAD v4.1 variant record for KIT NM_000222.3:c.2009C>T: total AC=3, total AN=1,613,636, AF=1.8591553485420504e-06, homozygotes=0, grpmax FAF=5.53e-06; highest observed subpopulation AF=3.3333333333333335e-05 in Admixed American individuals, 2/60,000 alleles.
• Generic ACMG/AMP calibration supplied for this case: BA1 stand-alone threshold >=0.05, attributed to ACMG/AMP 2015 (PMID:25741868).

Sources

Reasoning

BS1 is not met on the available population data. The generic default threshold is allele frequency >=0.01, while gnomAD v4.1 reports grpmax FAF=5.53e-06 and total AF=1.8591553485420504e-06 from 3/1,613,636 alleles. These values are several orders of magnitude below the default BS1 threshold, with no elevated adequately sampled ancestry frequency requiring a maximum-credible-frequency calculation. The gnomAD v2.1 total AF is likewise very low at 7.0808992742078246e-06 (2/282,450 alleles).

Rule

Allele frequency is greater than expected for the disorder.

Evidence considered

• gnomAD v4.1 variant record for KIT NM_000222.3:c.2009C>T: grpmax FAF=5.53e-06; total AF=1.8591553485420504e-06 from 3/1,613,636 alleles; highest observed subpopulation AF=3.3333333333333335e-05 in Admixed American individuals from 2/60,000 alleles.
• gnomAD v2.1 variant record: total AF=7.0808992742078246e-06 from 2/282,450 alleles; highest observed Finnish subpopulation AF=3.982477100756671e-05 from 1/25,110 alleles; grpmax FAF was not reported for v2.1.
• Generic ACMG/ClinGen-SVI calibration supplied for this case: BS1 default threshold >=0.01; per-gene maximum-credible-frequency derivation is preferred under Whiffin et al. 2017 (PMID:28518168).

Sources

Reasoning

The reviewed variant-specific functional studies do not show no damaging effect on KIT function. Instead, they consistently report constitutive or retained phosphorylation, altered kinase kinetics, increased catalytic efficiency, imatinib resistance, and drug-sensitive oncogenic signaling for KIT p.(Thr670Ile) in cellular and biochemical systems. Therefore, the evidence is directionally opposite to BS3 and cannot support a benign functional criterion.

Rule

Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.

Evidence considered

• The reviewed studies consistently show KIT T670I phosphorylation, altered catalytic kinetics, increased catalytic efficiency, imatinib resistance, or oncogenic signaling; none demonstrates preserved normal KIT function in a validated benign assay.
• The functional results are damaging-effect findings and therefore do not satisfy the direction of evidence required for BS3.

Sources

Reasoning

The variant is a missense substitution, so BP4 must be assessed through REVEL only; SpliceAI is not an alternative BP4 path for this variant. The REVEL score is 0.895, which is above the supplied BP4 supporting upper cutoff of <= 0.29 and lies in the deleterious/neutral gray zone rather than meeting any BP4 threshold. The SpliceAI max delta of 0.177 is not used for a missense BP4 decision, and BayesDel has no generic calibration.

Rule

BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant. ... An indeterminate result on the applicable path means PP3/BP4 are simply not met. It does not license reaching across to the other path's score - a missense variant whose REVEL sits in the gray zone gets no BP4, however clean its SpliceAI delta is. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)

Evidence considered

• The case summary identifies NM_000222.3:c.2009C>T as the missense variant p.(Thr670Ile), so REVEL is the applicable BP4 path; SpliceAI is not counted for BP4.
• Local REVEL predictor lookup (source_registry key revel) reports a REVEL score of 0.895.
• The supplied ClinGen SVI REVEL calibration assigns BP4 supporting at <= 0.29, BP4 moderate at <= 0.183, and BP4 strong at <= 0.016; REVEL 0.895 meets none of these thresholds. The calibration is Pejaver et al. 2022, PMID:36413997.
• BayesDel is not used because the governing prompt states that no generic ACMG-strength calibration is established for BayesDel.

Sources

Reasoning

The governing rule requires the variant to be found in a case with an alternate molecular basis for disease. The extracted evidence reports KIT T670I as an acquired secondary mutation in imatinib-resistant GISTs, including one tumor with a baseline KIT deletion, but this is a somatic tumor-resistance context and does not establish that the queried variant was found in a constitutional disease case with an alternate molecular basis. The available evidence therefore does not satisfy BP5 for this germline interpretation.

Rule

Variant found in a case with an alternate molecular basis for disease.

Evidence considered

• Debiec-Rychter et al. (PMID:15685537), case 14/Table 2: the tumor carried baseline KIT del WK557–558 plus acquired KIT-T670I; the paper frames T670I as secondary imatinib resistance in a tumor cohort.
• This somatic tumor co-occurrence is not evidence of an alternate molecular basis for a constitutional disease phenotype in the queried case.

Still missing

• A documented disease case showing the exact variant and an independent alternate molecular basis for that disease would be needed.

Sources

Reasoning

The governing rule requires a reputable source to recently report the exact variant as benign when the evidence is unavailable for independent evaluation. ClinVar variation 376058 has two exact-variant clinical-laboratory submissions, both Uncertain significance, and zero expert-panel submissions; no exact-variant reputable benign or likely-benign classification is present. Therefore BP6 is not met.

Rule

Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.

Evidence considered

• ClinVar variation 376058 exactly matches NM_000222.3:c.2009C>T (p.Thr670Ile); both submissions are Uncertain significance and expert-panel submissions = 0.
• No reputable exact-variant benign or likely-benign report was identified in the supplied ClinVar record or literature.

Sources

Reasoning

PS2 cannot be assessed because the available evidence does not document a proband with a disease-relevant phenotype, absence of family history, or confirmed maternity and paternity for this variant. ClinVar records germline submissions but provides no trio or parental testing results.

Rule

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.

Evidence considered

• ClinVar variation 376058 lists two germline clinical-testing submissions for NM_000222.3:c.2009C>T (p.Thr670Ile), but the record contains no trio results, parental genotypes, maternity or paternity confirmation, or family-history assessment.

Still missing

• Document the proband's disease-relevant phenotype and family history.
• Provide molecular confirmation of the variant in the proband and both biological parents, including confirmed maternity and paternity.

Sources

Reasoning

The governing rule requires that the prevalence in affected individuals be significantly increased compared with controls and specifies RR or OR >5.0 with a confidence interval excluding 1.0. The literature-pass PS4 leads (PMID:15236194 and PMID:25394175) were checked as leads: PMID:15236194 is a single-patient report of acquired KIT T670I resistance in a GIST, without a control group, and PMID:25394175 is a cancer-predisposition referral guideline rather than an exact-variant case-control study. The directly extracted cohort evidence reports T670I in 3 of 26 progressive, imatinib-treated GISTs, but these are somatic tumor observations and cannot be validly compared with germline gnomAD frequencies as matched controls for this germline interpretation. Therefore no valid case-control counts, OR/RR, and 95% CI meeting the rule are available.

Rule

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.

Evidence considered

• Debiec-Rychter et al. (PMID:15685537), Results/Table 2: KIT T670I was found in 3 of 26 progressive GISTs after imatinib treatment; this is a treated-tumor cohort, not a germline case-control study.
• Heinrich et al. (PMID:16954519), Table 2/patient 24: T670I was identified in 2 of 3 samples from one patient with secondary imatinib resistance; no unaffected control comparison is reported.
• gnomAD v4.1 reports 3/1,613,636 alleles, but this population germline frequency is not a valid control comparator for the somatic tumor observations above.
• The literature-pass PS4 leads PMID:15236194 and PMID:25394175 were specifically reviewed as required; neither supplies a valid exact-variant case-control comparison.

Still missing

• A valid germline case-control study with exact-variant affected and control counts or matched-ancestry frequencies is needed.
• The PMID:15236194 full text or abstract was not available in the case materials for independent audit; the available record identifies a single GIST patient, not a control study.
• The PMID:25394175 lead is a general referral guideline and does not provide exact-variant case-control data.

Sources

Reasoning

No germline affected-proband observation documents KIT c.2009C>T (p.Thr670Ile) in trans with a pathogenic variant, and no parental or offspring testing establishes phase. The available variant-specific publications describe acquired somatic KIT T670I in imatinib-resistant gastrointestinal stromal tumors, including tumors with primary KIT mutations, but do not provide germline inheritance or phase evidence for this case.

Rule

For recessive disorders, detected in trans with a pathogenic variant

Evidence considered

• PMID:15685537, Results/Molecular Analysis and Table 2, cases 13-15: KIT T670I was reported as an acquired secondary mutation in progressive imatinib-resistant GISTs; the report does not establish germline inheritance or parental phase.
• PMID:16954519, Results, 'Secondary Kinase Mutations Lead to Imatinib Resistance In Vitro' and Table 2, patient 24: KIT T670I was reported with primary KIT mutations in resistant tumors; the study does not establish germline trans phase or affected-proband inheritance.
• Case evidence: no documented parental/offspring testing, phase result, or affected-proband germline observation was found for this variant.

Still missing

• A confirmed recessive disease context and inheritance mode for KIT are not documented.
• An affected proband with the variant and a pathogenic variant in trans is not documented.
• Parental or offspring testing establishing phase is not documented.

Sources

Reasoning

PM6 cannot be assessed because no case-level evidence establishes that this variant is assumed de novo. The available ClinVar record identifies germline submissions but does not report parental testing, maternity or paternity status, or a disease-relevant proband phenotype.

Rule

Assumed de novo, but without confirmation of paternity and maternity.

Evidence considered

• ClinVar variation 376058 contains two germline clinical-testing submissions, but no submission-level documentation of de novo status, parental genotypes, parentage confirmation, or disease phenotype is available.

Still missing

• Provide case-level evidence that the variant occurred de novo in an affected proband.
• Document which parentage or parental genotype information is unavailable.

Sources

Reasoning

PP1 cannot be assessed because no affected relatives, informative meioses, genotype-phenotype co-segregation, or family pedigree data are reported for this variant. The available variant-specific literature concerns acquired somatic KIT mutations in GIST rather than germline familial segregation.

Rule

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.

Evidence considered

• ClinVar variation 376058 provides no family segregation data for the germline submission.
• Variant-specific studies report KIT T670I as an acquired secondary mutation in imatinib-resistant GIST or assess engineered constructs, not familial germline co-segregation: PMID:15685537, PMID:16751810, and PMID:16954519.

Still missing

• Provide a pedigree with phenotypes and variant testing results for affected and unaffected relatives.
• Provide the number of informative meioses and the variant's transmission pattern.

Sources

Reasoning

The supplied evidence does not establish both required gene-level conditions: a low rate of benign missense variation and missense variants as a common disease mechanism for the relevant inherited KIT disorder. Somatic GIST recurrence and the rarity of this individual variant do not substitute for those gene-level data.

Rule

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

Still missing

• A validated gene-level assessment showing a low rate of benign KIT missense variation is needed.
• A validated disease-mechanism assessment showing that missense variants commonly cause the relevant inherited KIT disorder is needed.

Reasoning

The governing rule requires a patient's phenotype or family history that is highly specific for a disease with a single genetic etiology. The case materials identify KIT p.(Thr670Ile) and tumor-resistance literature, but provide no patient phenotype, family history, or highly specific single-gene clinical presentation for this case. The available GIST papers describe somatic tumor biology and treatment resistance rather than a specific inherited phenotype.

Rule

Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.

Evidence considered

• The case summary provides the molecular variant and generic KIT/GIST context but no patient phenotype or family history.
• The extracted GIST publications describe somatic tumor mutation and imatinib resistance, not a highly specific inherited phenotype.

Still missing

• Patient-level phenotype and family-history data are required to assess PP4.

Sources

Reasoning

BS2 cannot be assessed from the available evidence. The governing rule requires observation in a healthy adult individual in the relevant zygosity for a disorder with full penetrance expected at an early age. The case evidence documents KIT p.Thr670Ile in somatic GIST and imatinib-resistance literature, but provides no observation of this variant in a healthy adult and no established early-onset, fully penetrant germline disorder context against which such an observation could be evaluated.

Rule

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.

Evidence considered

• Case summary identifies KIT NM_000222.3:c.2009C>T (p.Thr670Ile) as a missense variant and ClinVar classification as uncertain significance; no healthy-adult carrier observation is documented.
• Variant-specific literature extracts describe T670I as a secondary mutation in progressive GISTs and do not provide healthy-adult population observations or a germline penetrance analysis: PMID:15685537, PMID:16954519, PMID:16751810, PMID:17545544, PMID:27527414.

Still missing

• A documented healthy adult carrying KIT NM_000222.3:c.2009C>T in the relevant zygosity.
• A defined germline KIT disorder with full penetrance expected at an early age for this variant and inheritance model.

Reasoning

BS4 cannot be assessed because no affected family members with negative testing for the variant are documented. The available literature and ClinVar record do not provide a pedigree, phenotype assessments of relatives, or non-segregation results; therefore lack of segregation cannot be distinguished from absence of family data.

Rule

Lack of segregation in affected members of a family.

Evidence considered

• ClinVar variation 376058 contains no pedigree, affected-relative testing, or non-segregation data for this variant.

Still missing

• Provide testing results and disease phenotypes for affected relatives.
• Document any confirmed affected non-carriers and evaluate possible phenocopies or genetic heterogeneity.

Sources

Reasoning

The supplied evidence does not establish that the relevant KIT disease is caused primarily by truncating variants. The available KIT literature concerns a missense kinase-domain resistance variant and does not provide a validated gene-level comparison showing a primarily truncating disease mechanism.

Rule

Missense variant in a gene for which primarily truncating variants are known to cause disease.

Still missing

• A validated KIT disease-mechanism review comparing truncating and missense pathogenic variants is needed.

Reasoning

No germline observation documents KIT c.2009C>T (p.Thr670Ile) in cis with a pathogenic variant, and the available evidence does not establish a fully penetrant dominant KIT disorder for applying the trans branch. Variant-specific publications report somatic acquired KIT T670I together with primary KIT mutations in resistant tumors, but do not establish germline cis/trans phase for this case.

Rule

Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.

Evidence considered

• PMID:15685537, Results/Molecular Analysis and Table 2, cases 13-15: KIT T670I was an acquired secondary tumor mutation, including with a primary KIT deletion; this does not establish germline cis or trans phase.
• PMID:16954519, Results, 'Secondary Kinase Mutations Lead to Imatinib Resistance In Vitro' and Table 2, patient 24: KIT T670I co-occurred with primary KIT mutations in resistant tumor samples; phase and germline inheritance were not established.
• Case evidence: no germline phase result or affected-proband observation meeting either BP2 branch was documented.

Still missing

• A confirmed fully penetrant dominant KIT disorder context is not documented.
• A germline pathogenic variant observed in trans or cis with the queried variant is not documented.
• Testing that establishes phase is not documented.

Sources