ALK c.3604G>A, p.Gly1202Arg

Reasoning

PS3 is met at strong strength. Three full-text functional studies directly evaluated ALK p.Gly1202Arg (G1202R) in engineered cell systems, including Ba/F3 survival and phospho-ALK assays, NIH3T3 and Ba/F3 cellular assays, a patient-derived SQSTM1-ALK G1202R cell line, and an EML4-ALK G1202R mouse xenograft. The variant produced a reproducible, biologically relevant resistance phenotype: it was highly refractory to crizotinib (IC50 382 nM versus 20 nM for wild-type ALK in the double-mutant comparison), reduced suppression of ALK phosphorylation, and conferred high-level resistance to multiple second-generation ALK inhibitors. In an orthogonal therapeutic-response model, PF-06463922 inhibited G1202R-driven ALK phosphorylation at IC50 77–113 nM, inhibited growth of a patient-derived G1202R cell line at 63 nM versus 1046 nM for crizotinib, and significantly inhibited G1202R xenograft growth. These variant-specific results, use of engineered models and wild-type or drug-response comparators, and concordance across biochemical, cellular, patient-derived, and in vivo assays support a damaging effect on the ALK gene product. The evidence is not documented as validated and reproducible in a clinical diagnostic laboratory, but the breadth and reproducibility of the in vitro and in vivo evidence support strong rather than moderate PS3.

Rule

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

Evidence considered

• Katayama et al. 2012 (PMID:22277784): engineered Ba/F3 cells expressing EML4-ALK G1202R showed crizotinib resistance and reduced suppression of ALK phosphorylation; the variant was identified in an acquired-resistance NSCLC cohort of 18 patients and tested against multiple ALK inhibitors.
• Shaw et al. 2015 (PMID:26144315): engineered NIH3T3 and Ba/F3 assays showed G1202R-driven ALK phosphorylation inhibition by PF-06463922 at IC50 77–113 nM; a patient-derived SQSTM1-ALK G1202R cell line had a growth IC50 of 63 nM versus 1046 nM for crizotinib, and an EML4-ALK G1202R xenograft showed significant tumor-growth inhibition.
• Nair et al. 2016 (PMID:26698910): Ba/F3 cell-survival assays measured crizotinib IC50 382 nM for ALK G1202R, compared with 20 nM for wild-type ALK in the reported double-mutant comparison; the G1202R-L1198F double mutant restored sensitivity to 31 nM.
• The studies used engineered cellular models, phospho-ALK readouts, cell-survival or proliferation endpoints, patient-derived cells, and a mouse xenograft, providing concordant biological evidence of an altered ALK product phenotype.

Still missing

• The studies are preclinical functional models rather than assays documented as validated and reproducible in a clinical diagnostic laboratory.
• The primary endpoint is altered ALK inhibitor sensitivity and signaling behavior, not a direct quantitative measurement of general ALK protein function.
• No BS3-type assay demonstrating normal protein function or normal splicing was identified.

Sources

Reasoning

PM2 is met at supporting strength under the supplied generic SVI threshold. The variant is absent from gnomAD v2.1 and the reported v2.1 non-cancer subset, while gnomAD v4.1 shows only 1/1613836 alleles, AF 6.19642e-07, with zero homozygotes. This AF is below the supplied <=0.0001 PM2 threshold; the available source does not indicate a governing VCEP or an exome-only/non-cancer rule that would require a different source.

Rule

PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)

Evidence considered

• gnomAD v4.1 all-comers: AF 6.19642e-07, 1/1613836 alleles, homozygotes 0; the observed AF is <=0.0001.
• gnomAD v2.1 and the reported v2.1 non-cancer subset: variant absent.
• No VCEP covers ALK in this case, so generic ACMG/AMP rules govern; the supplied PM2 calibration assigns supporting strength at <=0.0001.

Sources

Reasoning

The variant is an exonic missense substitution, NM_004304.5:c.3604G>A (p.Gly1202Arg), so the governing generic PP3/BP4 path is REVEL only; SpliceAI is not used for a missense interpretation. REVEL is 0.919, meeting the published generic PP3 moderate threshold of >=0.773 and not the strong threshold of >=0.932. The REVEL calibration thresholds are from the ClinGen SVI calibration by Pejaver et al. 2022 (PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established, and the SpliceAI score is not counted on this missense path.

Rule

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).

Evidence considered

• Variant consequence and location: NM_004304.5:c.3604G>A is an exonic missense variant in exon 23 with predicted protein change p.Gly1202Arg.
• Applicable predictor path: REVEL only for this missense variant; SpliceAI is excluded because its splice prediction does not assess tolerance of the amino-acid substitution.
• Local REVEL lookup: score 0.919 for the variant.
• Generic calibrated thresholds supplied for this case: PP3 moderate >=0.773 and PP3 strong >=0.932; REVEL 0.919 therefore supports PP3 at moderate strength. Threshold source: ClinGen SVI REVEL calibration, Pejaver et al. 2022, PMID:36413997.
• BayesDel score 0.397708 was not used because the governing generic rules provide no established ACMG-strength calibration for BayesDel.

Sources

Reasoning

BP5 is supported because PMID:22277784 verifies the exact G1202R variant in acquired crizotinib-resistant ALK-positive NSCLC tumors, where the disease context already includes an ALK rearrangement and the paper characterizes G1202R as a secondary resistance mutation. Thus the reported case has an alternate molecular basis for the cancer (the ALK rearrangement), rather than the queried secondary G1202R being the sole molecular basis. This is somatic tumor evidence and should be reviewed for applicability if the target interpretation is restricted to a germline disease context.

Rule

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

Evidence considered

• Katayama et al. (PMID:22277784): the exact G1202R variant was identified as a secondary mutation among acquired crizotinib-resistant ALK-positive NSCLC tumors; the study's cohort and title establish the ALK-rearranged cancer context, and its direct report states that G1202R was one of the resistance mutations.
• The paper extraction describes G1202R as a secondary mutation in ALK-positive tumors and reports sequencing of ALK exons 20–28 after acquired resistance.

Still missing

• Confirm that the BP5 disease context is intended to include the reported somatic ALK-rearranged NSCLC rather than only a germline disease interpretation.

Sources

Reasoning

The variant is NM_004304.5:c.3604G>A, p.Gly1202Arg. The literature reports this exact amino-acid change as a somatic ALK inhibitor-resistance mutation in ALK-rearranged tumors, but the available evidence does not establish it as a previously established pathogenic variant for the disease context. ClinVar contains conflicting single-laboratory classifications, including uncertain significance and likely pathogenic, without an expert-panel determination. Therefore the required previously established pathogenic comparator is not demonstrated.

Rule

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

Evidence considered

• Katayama et al. 2012 (PMID:22277784) reports ALK G1202R as a secondary mutation in crizotinib-resistant ALK-positive NSCLC, but this is somatic resistance evidence rather than an established pathogenic germline classification.
• ClinVar variation 376134 is an exact match for NM_004304.5:c.3604G>A (p.Gly1202Arg) and has single-laboratory submissions including uncertain significance and likely pathogenic, with no expert-panel submission.

Still missing

• An established pathogenic classification for an alternate nucleotide change producing ALK p.Gly1202Arg is not available.

Sources

Reasoning

PP5 requires a reputable source to recently report the exact variant as pathogenic when the underlying evidence is unavailable for independent evaluation. The exact ClinVar record has no expert-panel submission: it contains three clinical-laboratory uncertain-significance submissions and one somatic likely-pathogenic submission without assertion criteria. The aggregate ClinVar label and non-expert laboratory assertions therefore do not satisfy the required exact-variant reputable-source trigger, and OncoKB is inconclusive.

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 376134: zero expert-panel submissions; three clinical-laboratory submissions classify the variant as uncertain significance, while one somatic submission is likely pathogenic with no assertion criteria.
• OncoKB reports an inconclusive curated oncogenicity label for ALK G1202R.

Sources

Reasoning

BS3 is not met. The available variant-specific functional studies do not show no damaging effect on ALK protein function or splicing; instead, they consistently demonstrate an altered G1202R phenotype, including crizotinib resistance, reduced phospho-ALK suppression, and resistance to multiple ALK inhibitors in cellular and in vivo models. No well-established normal-function or normal-splicing assay for this variant was identified.

Rule

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

Evidence considered

• PMID:22277784: ALK G1202R reduced suppression of ALK phosphorylation and conferred resistance in engineered Ba/F3 cells.
• PMID:26144315: ALK G1202R showed resistance-associated cellular and xenograft behavior, while PF-06463922 specifically inhibited the mutant-driven phenotype.
• PMID:26698910: ALK G1202R was highly refractory to crizotinib in Ba/F3 cell assays, with IC50 382 nM.

Still missing

• No well-established assay demonstrating normal ALK protein function or normal splicing for p.Gly1202Arg was identified.
• The available studies do not provide a benign functional control suitable for BS3.

Sources

Reasoning

The variant is an exonic missense substitution, so BP4 must be judged using the REVEL path only. REVEL is 0.919, which is above the generic BP4 supporting cutoff of <=0.29 and therefore does not support no impact. The SpliceAI max delta of 0.002 is not considered for BP4 because splice predictions are not evidence for a missense variant's tolerance, and BayesDel is not used because no generic ACMG-strength calibration is established. The REVEL calibration thresholds are from the ClinGen SVI calibration by Pejaver et al. 2022 (PMID:36413997).

Rule

Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)

Evidence considered

• Variant consequence and location: NM_004304.5:c.3604G>A is an exonic missense variant in exon 23 with predicted protein change p.Gly1202Arg.
• Applicable predictor path: REVEL only for this missense variant; SpliceAI is excluded because a no-splice-impact prediction cannot establish no impact from an amino-acid substitution.
• Local REVEL lookup: score 0.919 for the variant.
• Generic calibrated threshold supplied for this case: BP4 supporting <=0.29; REVEL 0.919 does not meet that threshold. Threshold source: ClinGen SVI REVEL calibration, Pejaver et al. 2022, PMID:36413997.
• BayesDel score 0.397708 was not used because the governing generic rules provide no established ACMG-strength calibration for BayesDel.

Sources

Reasoning

BP6 requires a reputable source to recently report the exact variant as benign when the underlying evidence is unavailable for independent evaluation. No exact-variant ClinVar expert-panel benign or likely-benign classification is present; the ClinVar record contains uncertain-significance clinical-laboratory submissions and a non-criteria somatic likely-pathogenic submission. Aggregate or non-expert assertions cannot trigger BP6.

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 376134 has no expert-panel submissions and no benign or likely-benign exact-variant assertion; the available laboratory classifications are uncertain significance or non-criteria likely pathogenic.

Sources

Reasoning

No reliable evidence is provided that this variant occurred de novo in an affected proband. The available case evidence does not document an affected proband's phenotype together with confirmed maternity and paternity, and no family-history assessment is available. The criterion therefore cannot be assessed; absence of parental testing documentation is not evidence against PS2.

Rule

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

Evidence considered

• The case evidence contains no documented proband-level parental testing, confirmed maternity, confirmed paternity, or family-history assessment for NM_004304.5:c.3604G>A (ALK p.Gly1202Arg).
• PMID:26698910 reports ALK G1202R in functional cell-line assays and explicitly states that the paper does not report a patient carrying G1202R, segregation data, or population-frequency data.

Still missing

• Affected proband phenotype and diagnosis must be documented.
• Variant testing results for both biological parents are needed.
• Maternity and paternity confirmation and family-history information are needed.

Sources

Reasoning

The governing PS4 definition requires that the prevalence of the variant in affected individuals be significantly increased compared with controls, with ACMG Note 1 specifying an RR or OR >5.0 and a confidence interval that does not include 1.0. PMID:22277784 was verified as reporting the exact ALK G1202R variant in 1 of 18 patients with acquired crizotinib-resistant ALK-positive NSCLC (the paper states, "Among the 18 crizotinib-resistant patients, we identified 4 (22%) with resistance mutations: 3 missense mutations (L1196M, G1202R, and S1206Y) and an amino acid (threonine) insertion mutation (1151Tins)"), but it provides no unaffected/control comparison or control frequency for G1202R. The literature packet's PS4-indexed sources were checked as leads; no verified exact-variant case-control counts sufficient to compute an OR and 95% CI were available. Therefore the required enrichment statistic and confidence interval cannot be assessed.

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

• Katayama et al. (PMID:22277784), Results: among 18 crizotinib-resistant ALK-positive NSCLC patients, 4 (22%) had resistance mutations including G1202R; the cohort is affected/resistant cases and does not provide unaffected controls or a control frequency for G1202R.
• The exact-variant paper extraction states that the paper reports no population-frequency data and no control comparison.

Still missing

• A verified unaffected/control count or matched-ancestry control frequency for exact ALK c.3604G>A/p.G1202R is required to compute an OR and 95% CI.

Sources

Reasoning

ALK p.Gly1202Arg is located in the solvent-front region of the ALK intracellular kinase domain, and the variant is repeatedly described in functional cancer-resistance studies as affecting the inhibitor-binding region. However, generic PM1 additionally requires a critical, well-established domain or hotspot without benign variation. The supplied evidence does not provide a systematic benign-variation assessment for the ALK kinase domain, so PM1 cannot be concluded under the complete generic rule.

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

• Ou et al. 2014 (PMID:24736079), Results/Discussion: ALK G1202R is located at the solvent front of the ALK kinase domain and is adjacent to the crizotinib-binding site; the paper reports resistance to multiple ALK inhibitors.
• Katayama et al. 2012 (PMID:22277784), Results and Discussion: ALK G1202R is a solvent-front mutation near the crizotinib-binding site and causes steric interference with inhibitor binding.
• No systematic benign-variation survey for the relevant ALK kinase-domain region is present in the supplied evidence.

Still missing

• Systematic evidence that the relevant ALK kinase-domain region lacks benign variation is unavailable.

Sources

Reasoning

PM3 cannot be assessed because the available evidence does not establish that ALK NM_004304.5:c.3604G>A (p.Gly1202Arg) occurs in a recessive disorder, nor does it document a pathogenic allele in trans, parental or offspring testing, or phase. The reviewed exact-variant literature describes G1202R as an acquired somatic resistance mutation in ALK-rearranged NSCLC rather than a germline affected-proband observation, and one extracted paper explicitly reports no segregation data.

Rule

For recessive disorders, detected in trans with a pathogenic variant ... This requires testing of parents (or offspring) to determine phase.

Evidence considered

• ClinVar exact-match record for NM_004304.5(ALK):c.3604G>A (p.Gly1202Arg) contains no documented phase, parental testing, affected-proband compound-heterozygous observation, or pathogenic in-trans partner for this assessment.
• Katayama et al. (PMID:22277784) reports G1202R among secondary mutations in crizotinib-resistant ALK-positive NSCLC tumors; this is a somatic resistance context and does not establish germline recessive inheritance or allelic phase.
• The extracted finding from PMID:26698910 states that the paper does not report a patient carrying G1202R, segregation data, or population-frequency data; therefore it supplies no PM3 phase evidence.

Still missing

• Disease-specific inheritance mode for the germline interpretation is not established in the available case evidence.
• No affected-proband report with a second pathogenic allele is documented.
• No parental or offspring testing establishes trans phase.
• No pathogenic cis/trans partner variant is identified for this case.

Sources

Reasoning

The variant changes glycine 1202 to arginine. The supplied same-residue comparator search contains no candidate variants and does not identify a different missense substitution at Gly1202 that has been determined to be pathogenic. The cancer literature documents the queried G1202R change itself, not a qualifying pathogenic alternate missense change at the same residue. Therefore PM5 cannot be assessed as met.

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 PM5 comparator collection reports zero total candidates and zero same-residue candidates for ALK p.Gly1202Arg.
• The available literature reports the queried G1202R substitution itself and does not establish a different pathogenic missense substitution at residue 1202.

Still missing

• A qualifying pathogenic alternate missense comparator at ALK residue 1202 is not identified.

Sources

Reasoning

No reliable evidence is provided for an assumed de novo variant in an affected patient. The available case evidence does not document an affected proband with negative parental testing or other evidence supporting de novo status without confirmed maternity and paternity. The criterion therefore cannot be assessed.

Rule

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

Evidence considered

• The case evidence contains no documented proband-level parental testing or other basis for assuming de novo status for NM_004304.5:c.3604G>A (ALK p.Gly1202Arg).
• PMID:26698910 reports functional ALK G1202R experiments and explicitly states that the paper does not report a patient carrying G1202R or segregation data.

Still missing

• Affected proband phenotype and diagnosis must be documented.
• Parental testing results or a documented basis for assuming de novo status are needed.
• Family-history information is needed.

Sources

Reasoning

No affected family members, informative meioses, or variant-positive and variant-negative relatives are documented. The available literature concerns somatic or functional ALK G1202R findings rather than familial cosegregation, so PP1 cannot be assessed.

Rule

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

Evidence considered

• The case evidence contains no pedigree, affected-relative genotypes, unaffected-relative genotypes, or informative meioses for NM_004304.5:c.3604G>A (ALK p.Gly1202Arg).
• The reviewed literature reports ALK G1202R in acquired-resistance tumors or experimental models and does not provide familial cosegregation data.

Still missing

• A pedigree with clinically characterized affected relatives is needed.
• Variant genotypes for affected and unaffected relatives are needed.
• Informative meioses and phenotype assessments are needed.

Sources

Reasoning

The variant is a missense substitution in ALK, but 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. The reported ALK G1202R studies concern somatic inhibitor resistance and do not provide a genome-wide or gene-level benign-missense rate or a disease-mechanism prevalence assessment suitable for PP2.

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.

Evidence considered

• The normalized consequence is missense, p.Gly1202Arg.
• The available functional papers address somatic ALK inhibitor resistance and do not establish the two gene-level PP2 prerequisites.

Still missing

• A gene-level assessment of ALK benign missense variation is unavailable.
• A disease-context assessment showing that missense variation is a common ALK disease mechanism is unavailable.

Reasoning

PP4 requires a patient's phenotype or family history that is highly specific for a disease with a single genetic etiology. The available exact-variant literature describes somatic ALK G1202R in acquired-drug-resistance NSCLC tumors and does not provide a phenotype or family-history assessment for this queried variant case that establishes such specificity. No sufficient patient phenotype/family-history evidence is available to assess PP4.

Rule

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

Evidence considered

• PMID:22277784 documents an acquired-resistance NSCLC tumor context for G1202R, not a specific germline phenotype or family-history pattern for PP4.

Still missing

• A clinical phenotype and family-history description for the evaluated patient, linked to a disease with a single genetic etiology, is required.

Sources

Reasoning

BA1 cannot be adjudicated from the required filtering allele frequency because gnomAD v4.1 reports grpmax FAF as null. The available all-comers total AF is 6.19642e-07 (1/1613836 alleles), far below the generic >=0.05 threshold, and gnomAD v2.1 and its non-cancer subset report the variant as absent; however, the instructed BA1 decision must use grpmax FAF rather than a popmax point estimate, so the missing FAF is a data gap rather than a met/not-met frequency result.

Rule

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

Evidence considered

• gnomAD v4.1 all-comers: total AF 6.19642e-07, 1/1613836 alleles, homozygotes 0; grpmax FAF is null.
• gnomAD v2.1 and the reported gnomAD v2.1 non-cancer subset: variant absent.
• Generic BA1 calibration supplied for this interpretation: >=0.05, attributed to ACMG/AMP 2015 (PMID:25741868). The required filtering FAF, not the population point estimate, is unavailable.

Still missing

• A reported gnomAD filtering grpmax FAF is required for the instructed BA1 adjudication.

Sources

Reasoning

BS1 cannot be finalized under the instructed frequency method because gnomAD v4.1 does not report a grpmax FAF. The observed all-comers AF is 6.19642e-07 (1/1613836 alleles), well below the generic 0.01 default, and the variant is absent from gnomAD v2.1 and its non-cancer subset. Nevertheless, a missing filtering FAF prevents the required FAF-based adjudication; no disease prevalence, penetrance, allelic heterogeneity, or maximum-credible-frequency calculation is supplied to replace that method.

Rule

Allele frequency is greater than expected for the disorder.

Evidence considered

• gnomAD v4.1 all-comers: total AF 6.19642e-07, 1/1613836 alleles, homozygotes 0; grpmax FAF is null.
• gnomAD v2.1 and the reported gnomAD v2.1 non-cancer subset: variant absent.
• Generic BS1 default supplied for this interpretation: >=0.01; the prompt requires consideration of maximum credible allele frequency using disorder prevalence, penetrance, and allelic heterogeneity before applying the default.

Still missing

• A reported grpmax FAF or a disorder-specific maximum-credible-frequency calculation with prevalence, penetrance, and allelic heterogeneity inputs is required.

Sources

Reasoning

The variant is observed once in gnomAD v4.1 and has zero homozygotes, but the population record does not establish that the carrier was a healthy adult, provide age, or document the expected full penetrance and early age of onset for a relevant ALK disorder. Therefore, the single heterozygous observation cannot satisfy BS2 without phenotype and age information.

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

• gnomAD v4.1: 1 alternate allele among 1613836 alleles, zero homozygotes; the record does not provide carrier phenotype or age.
• gnomAD v2.1: variant absent.

Still missing

• Verified healthy-adult status and age of the carrier are unavailable.
• The relevant disorder's expected penetrance and age of onset are not documented for this observation.

Sources

Reasoning

No affected family members with documented absence of the variant are identified. Because neither a segregating family nor a defined non-segregating affected relative is available, lack of segregation cannot be established and BS4 cannot be assessed.

Rule

Lack of segregation in affected members of a family.

Evidence considered

• The case evidence contains no affected-relative testing or family-level non-segregation observation for NM_004304.5:c.3604G>A (ALK p.Gly1202Arg).
• The reviewed literature does not document an affected family member who lacks the variant.

Still missing

• A clinically characterized affected family is needed.
• Variant testing results for affected relatives are needed.
• Phenocopy and alternative-variant explanations should be evaluated if non-segregation is later observed.

Sources

Reasoning

The variant is missense, so the criterion's variant-type premise is satisfied. However, the supplied evidence does not establish that ALK is a gene for which primarily truncating variants are known to cause the relevant disease. The available ALK literature instead emphasizes kinase-domain missense substitutions in somatic cancer resistance, which is not sufficient to prove or disprove the required gene-level predominance for BP1.

Rule

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

Evidence considered

• The normalized consequence is missense, p.Gly1202Arg.
• The supplied ALK papers describe kinase-domain missense resistance mutations, but do not provide the disease-specific variant-spectrum analysis required for BP1.

Still missing

• An authoritative disease-specific comparison of truncating versus missense ALK pathogenic variants is unavailable.

Reasoning

BP2 cannot be assessed because the available evidence does not document this variant in trans with a pathogenic variant in a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern. The exact-variant papers reviewed describe somatic acquired resistance in ALK-rearranged NSCLC and provide no germline cis/trans testing or pathogenic partner observation; the extracted evidence also specifically notes absent segregation data.

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

• ClinVar exact-match record for NM_004304.5(ALK):c.3604G>A (p.Gly1202Arg) does not document a pathogenic cis/trans partner or phase result usable for BP2.
• Katayama et al. (PMID:22277784) reports G1202R as a secondary mutation in acquired crizotinib-resistant ALK-positive NSCLC; this somatic tumor observation does not establish germline cis/trans configuration with a pathogenic variant.
• The extracted finding from PMID:26698910 states that no patient carrying G1202R, segregation data, or population-frequency data were reported, leaving BP2's phase requirement unmet.

Still missing

• No affected-proband germline observation documents a pathogenic variant in trans or cis.
• No parental, offspring, tumor-normal, or other assay establishes phase with a pathogenic partner.
• The required fully penetrant dominant disease context for the trans pathway is not established in the available case evidence.

Sources