EGFR c.2369C>T, p.(Thr790Met)

Reasoning

Multiple independent, well-controlled functional studies directly evaluate EGFR T790M, corresponding to NM_005228.5:c.2369C>T. Patient-derived tumor sequencing and an independent PCR-RFLP assay linked the variant to acquired resistance, while engineered EGFR constructs, phospho-EGFR and total-EGFR controls, inhibitor-response assays, and NSCLC cell-line viability assays demonstrated persistent kinase signaling and markedly reduced gefitinib/erlotinib sensitivity. Biochemical and structural assays further showed altered ATP/inhibitor behavior and increased kinase activity in T790M-containing EGFR. The evidence is concordant across molecular, cellular, biochemical, and clinical-resistance models and supports a damaging gain-of-function/resistance effect for this variant.

Rule

Generic ACMG/AMP PS3: well-established functional studies supportive of a damaging effect. The concordant direct variant assays, appropriate controls, independent assay systems, and reproducibility justify strong strength in this case.

Evidence considered

• PMID:15728811 directly identified the c.2369C>T/p.T790M alteration in a relapse biopsy and confirmed it by repeat PCR sequencing and cDNA sequencing; transiently transfected EGFR constructs showed persistent phosphorylation and high-level gefitinib resistance, with comparison constructs and inhibitor treatment controls.
• PMID:15737014 identified c.2369C>T/p.T790M in progressing lesions from three patients, absent from corresponding pretreatment samples, and independently confirmed it with a mutation-specific PCR-RFLP assay. Engineered wild-type, L858R, and exon 19 deletion EGFR constructs were tested with total-EGFR, phospho-EGFR, phosphotyrosine, and actin controls; T790M prevented gefitinib/erlotinib inhibition. H1975 cells containing T790M plus L858R were approximately 100-fold less sensitive to gefitinib than L858R-only H3255 cells.
• PMID:18227510 evaluated EGFR T790M in biochemical kinase, ATP Michaelis-Menten, inhibitor-binding, and crystallographic assays. It reported restoration of near-wild-type ATP affinity in L858R/T790M, approximately fivefold increased kinase activity for T790M, and preserved binding of reversible inhibitors with altered inhibitor interaction; the extracted paper did not state the exact c.2369C>T nucleotide notation, so it is supportive at the T790M protein level.
• PMID:34526717 included T790M in in-vitro drug-sensitivity screening of EGFR-mutant cell lines and reported sensitivity to third-generation but not first- or second-generation EGFR TKIs; this independently supports a reproducible functional drug-response effect, although it is not a variant-specific germline assay.
• No source provided a validated benign functional result for EGFR T790M; absence of benign assay evidence was not used to support PS3.

Still missing

• No EGFR-specific VCEP/ClinGen specification was available; generic ACMG/AMP functional-evidence calibration was used.
• The available assays primarily establish oncogenic kinase activity and tyrosine-kinase-inhibitor resistance rather than a germline disease-specific endpoint.

Sources

Reasoning

EGFR p.(Thr790Met) lies at residue 790 in the EGFR tyrosine-kinase catalytic cleft/kinase domain and is independently documented as a statistically significant hotspot. Functional structural and biochemical literature identifies Thr790 as the kinase gatekeeper and shows that the T790M substitution alters ATP affinity and drug response. No gene-specific VCEP domain_tables entry is present, so the generic ACMG/AMP PM1 framework is used.

Rule

Generic ACMG/AMP PM1 supports a variant located in a well-established critical functional domain or hotspot with low benign variation; default strength is moderate when no disease-specific specification assigns another strength.

Evidence considered

• PMID:15728811 states that T790M changes threonine 790 in the catalytic cleft of the EGFR tyrosine-kinase domain and demonstrates a functional resistance effect.
• PMID:18227510 characterizes Thr790 as the EGFR kinase gatekeeper and reports altered ATP affinity and kinase activity for T790M in biochemical and structural studies.
• The hotspot evidence reports that this variant lies in a statistically significant hotspot.
• vcep_materials.json reports no applicable EGFR CSPEC and an empty domain_tables object; therefore no authoritative gene-specific domain list was available to check.

Still missing

• No EGFR-specific VCEP framework or authoritative domain_tables entry was available in this case.
• The case bundle does not provide a formal benign-variation exclusion analysis for the kinase-domain interval.

Sources

Reasoning

PM2 is met at supporting strength. The variant is present at an extremely low frequency in gnomAD v2.1 (10/282862 alleles; AF 3.53529e-05; group maximum FAF 4.078e-05) and gnomAD v4.1 (16/1614100 alleles; AF 9.91264e-06; group maximum FAF 1.746e-05), with no observed homozygotes. The highest ancestry-specific frequencies remain below 0.1% (0.01602% in gnomAD v2.1 and 0.00534% in gnomAD v4.1), satisfying the generic rarity threshold used for PM2. The gnomAD-Canada result was unavailable/absent because the query timed out, but this does not negate the large gnomAD v2/v4 population evidence.

Rule

Generic ACMG/AMP PM2 rule: supporting evidence when the variant is absent or extremely rare in population databases; under the operating threshold used here, maximum credible allele frequency must be below 0.1%, with ancestry-specific frequencies considered.

Evidence considered

• gnomAD v2.1 reports 10/282862 alleles, AF 3.53529e-05, group maximum FAF 4.078e-05, highest ancestry AF 0.000160192 (0.01602%), and zero homozygotes.
• gnomAD v4.1 reports 16/1614100 alleles, AF 9.91264e-06, group maximum FAF 1.746e-05, highest ancestry AF 5.33803e-05 (0.00534%), and zero homozygotes.
• Both datasets are far below the generic PM2 rarity threshold of 0.1% and show no homozygotes.
• gnomAD-Canada v1.0 was not available for this variant in the case bundle because the local query timed out; it provides no contrary frequency evidence.

Still missing

• No EGFR-specific disease-prevalence and penetrance-based maximum credible allele-frequency calculation was available.
• gnomAD-Canada v1.0 could not be evaluated successfully because the query timed out.

Sources

Reasoning

EGFR c.2369C>T is a missense variant (p.(Thr790Met)); no EGFR VCEP/CSPEC PP3 rule is available, so the generic missense-only REVEL path applies. REVEL 0.529 is within the 0.250–0.750 gray zone and does not meet PP3.

Rule

Generic ACMG/AMP fallback: missense variants use REVEL only; PP3 supporting if REVEL >0.750, BP4 supporting if REVEL <0.250; otherwise neither criterion is met.

Evidence considered

• The case evidence identifies the consequence as missense, p.(Thr790Met), and reports REVEL 0.529.
• No EGFR CSPEC, VCEP material, or gene-specific PP3/BP4 rule was found in the governing case materials.
• Generic missense calibration uses REVEL only: PP3 requires a score >0.750 and BP4 requires a score <0.250; this calibrated REVEL framework is published by ClinGen SVI (PMID:36413997). The observed score is in neither actionable range.
• SpliceAI max delta 0.002 was not used because splice prediction is not an admissible PP3/BP4 mechanism for this missense substitution. BayesDel was not used because no verified published calibration threshold is available in this pipeline.

Sources

Reasoning

ClinVar has exact-variant expert-panel submissions from ClinPGx, but both are classified as drug response rather than Pathogenic or Likely pathogenic. The Pathogenic/Likely pathogenic submissions are not expert-panel assertions and cannot trigger PP5.

Rule

Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.

Evidence considered

• The exact-variant ClinPGx expert-panel submissions are drug-response assertions for erlotinib efficacy and gefitinib efficacy.
• The exact-variant Pathogenic and Likely pathogenic ClinVar submissions in the bundle are ordinary laboratory submissions, not expert-panel assertions.

Still missing

• An exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion would be required.

Sources

Reasoning

BA1 is not met. The highest observed population frequency is 0.000160192 (0.01602%) in gnomAD v2.1 and 0.0000533803 (0.00534%) in gnomAD v4.1, far below the generic BA1 threshold of greater than 1%. No ancestry-specific frequency approaches the BA1 threshold.

Rule

Generic ACMG/AMP population-frequency rule: BA1 requires a population allele frequency above 1%; evaluate the maximum credible ancestry-specific frequency rather than only the aggregate frequency.

Evidence considered

• gnomAD v2.1 reports 10/282862 alleles, total AF 3.53529e-05, zero homozygotes, and highest ancestry AF 0.000160192 (African/African American).
• gnomAD v4.1 reports 16/1614100 alleles, total AF 9.91264e-06, zero homozygotes, and highest ancestry AF 5.33803e-05 (African/African American).
• Under the generic ACMG/AMP operating thresholds used here, BA1 requires allele frequency greater than 1%; the observed frequencies are substantially lower.

Still missing

• No EGFR-specific disease-prevalence or penetrance-based maximum credible allele-frequency model was available; the generic threshold was therefore used.

Sources

Reasoning

BS1 is not met. The highest observed population frequency is 0.000160192 (0.01602%) in gnomAD v2.1 and 0.0000533803 (0.00534%) in gnomAD v4.1, both below the generic BS1 threshold of greater than 0.3%. The variant is therefore not observed at a frequency too high for the relevant disease context under the available population data.

Rule

Generic ACMG/AMP population-frequency rule: BS1 requires an allele frequency above 0.3% when the observed frequency is too high for the disease context; assess the highest credible ancestry-specific frequency.

Evidence considered

• gnomAD v2.1 reports aggregate AF 3.53529e-05, group maximum FAF 4.078e-05, and highest ancestry AF 0.000160192 (African/African American), with zero homozygotes.
• gnomAD v4.1 reports aggregate AF 9.91264e-06, group maximum FAF 1.746e-05, and highest ancestry AF 5.33803e-05 (African/African American), with zero homozygotes.
• Under the generic ACMG/AMP operating thresholds used here, BS1 requires allele frequency greater than 0.3%; the observed frequencies are substantially lower.

Still missing

• No EGFR-specific disease-prevalence, penetrance, inheritance, or maximum credible allele-frequency model was available; the generic threshold was therefore used.

Sources

Reasoning

BS2 is not met. gnomAD v2.1 and gnomAD v4.1 each report zero homozygotes for NM_005228.5:c.2369C>T (p.Thr790Met). There is no evidence in the case bundle of multiple unaffected individuals carrying the variant in the homozygous state or of unaffected adults carrying a variant expected to cause a fully penetrant dominant disorder.

Rule

Generic ACMG/AMP BS2 rule: supporting benign evidence requires observation in multiple unaffected individuals, including homozygotes for a recessive condition or adults for a fully penetrant dominant condition, as appropriate to the disease model.

Evidence considered

• gnomAD v2.1 reports homozygotes = 0 overall and zero homozygotes in the highest-frequency African/African American subgroup.
• gnomAD v4.1 reports homozygotes = 0 overall and zero homozygotes in the highest-frequency African/African American subgroup.
• No qualifying unaffected homozygote observation is present in the provided case evidence.

Still missing

• No disease-specific penetrance model or targeted unaffected-control cohort beyond gnomAD was available.

Sources

Reasoning

EGFR c.2369C>T is a missense variant (p.(Thr790Met)); no EGFR VCEP/CSPEC BP4 rule is available, so the generic missense-only REVEL path applies. REVEL 0.529 is within the 0.250–0.750 gray zone and does not meet BP4.

Rule

Generic ACMG/AMP fallback: missense variants use REVEL only; PP3 supporting if REVEL >0.750, BP4 supporting if REVEL <0.250; otherwise neither criterion is met.

Evidence considered

• The case evidence identifies the consequence as missense, p.(Thr790Met), and reports REVEL 0.529.
• No EGFR CSPEC, VCEP material, or gene-specific PP3/BP4 rule was found in the governing case materials.
• Generic missense calibration uses REVEL only: PP3 requires a score >0.750 and BP4 requires a score <0.250; this calibrated REVEL framework is published by ClinGen SVI (PMID:36413997). The observed score is in neither actionable range.
• SpliceAI max delta 0.002 was not used because splice prediction is not an admissible PP3/BP4 mechanism for this missense substitution. BayesDel was not used because no verified published calibration threshold is available in this pipeline.

Sources

Reasoning

No exact-variant ClinVar expert-panel Benign or Likely benign classification is present. The only exact-variant expert-panel assertions are drug-response classifications; non-expert submissions cannot trigger BP6.

Rule

Apply BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign classification.

Evidence considered

• The exact-variant ClinPGx expert-panel submissions are drug-response assertions, not Benign or Likely benign classifications.
• No expert-panel Benign or Likely benign classification is reported for this exact variant.

Still missing

• An exact-variant ClinVar expert-panel Benign or Likely benign assertion would be required.

Sources

Reasoning

The variant is EGFR p.(Thr790Met), and the literature documents this exact substitution in somatic drug-resistance and functional contexts. However, the available evidence does not establish the same amino-acid change as a pathogenic germline variant for an applicable EGFR germline disease, and the ClinVar expert-panel record is for drug response rather than a germline disease assertion. The exact-change requirement is therefore not safely met for PS1 in this assessment.

Rule

Generic ACMG/AMP PS1 requires the same amino-acid change as an established pathogenic variant; disease context and pathogenicity must be applicable to the assessed condition.

Evidence considered

• PMID:15728811 explicitly reports EGFR T790M as an acquired second mutation in recurrent gefitinib-resistant cancer and confirms the c.2369C>T substitution by sequencing and functional assays.
• PMID:15737014 reports T790M in progressing lesions after EGFR-TKI treatment and shows resistance in biochemical and cell-based assays.
• ClinVar variation 16613 has an expert-panel drug-response record and additional single-submitter pathogenic/likely pathogenic submissions, but the available record does not provide a validated germline disease-specific pathogenic assertion suitable for PS1 here.

Still missing

• A validated pathogenic germline EGFR p.(Thr790Met) record or applicable disease-specific assertion is not available in the case evidence.
• The available exact-variant literature is predominantly somatic oncology and drug-response evidence, not germline disease evidence.

Sources

Reasoning

No proband-level de novo observation is documented in the case-evidence bundle. There is no parental testing, parental genotype, maternity/paternity confirmation, or explicit de novo statement for EGFR NM_005228.5:c.2369C>T (p.Thr790Met). Therefore PS2 cannot be assessed.

Rule

Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history, with maternity and paternity confirmed; stronger application requires appropriate parental testing and phenotype assessment.

Evidence considered

• The case-evidence bundle identifies the variant as EGFR NM_005228.5:c.2369C>T (p.Thr790Met), but contains no proband pedigree, parental genotype results, or de novo assessment.
• The available paper extractions concern somatic/acquired EGFR T790M in lung cancer and do not provide a germline proband-parent de novo observation relevant to PS2.

Still missing

• Documented proband genotype and phenotype
• Both biological parents tested for the variant
• Confirmed maternity and paternity or equivalent family relationships
• Explicit de novo result with assay details

Reasoning

The reviewed evidence documents EGFR T790M in acquired EGFR-TKI resistance, but does not provide a germline case-control comparison or an odds ratio establishing statistically significant enrichment in an affected population versus controls.

Rule

Generic ACMG/AMP PS4 requires statistically increased prevalence of the variant in affected individuals compared with controls.

Evidence considered

• PMID:15737014 reports T790M in progressing lesions from three treated patients and states that acquired clinical resistance was associated with T790M; it supplies no unaffected-control comparator or germline prevalence estimate.
• PMID:29151359 states that T790M is detected in 50% or more of EGFR-mutated NSCLC patients after progression on first- or second-generation EGFR-TKIs. This is prevalence in a treatment-selected progression setting, not affected-versus-control enrichment for germline ACMG PS4.

Still missing

• A phenotype-defined germline case-control or adequately powered cohort study reporting exact-variant counts in affected individuals and ancestry-matched controls is needed.
• The available reports concern tumors after EGFR-TKI exposure and cannot establish germline disease prevalence enrichment.

Sources

Reasoning

No applicable EGFR-specific VCEP framework was available, so the generic ACMG/AMP PM3 concept was considered. The available evidence does not document the variant in an affected individual with a second established pathogenic variant in trans, nor does it establish a recessive EGFR disease context. Reports of EGFR p.(T790M) as a germline lung-cancer susceptibility allele and as an acquired somatic resistance mutation do not provide qualifying biallelic phase evidence.

Rule

Generic ACMG/AMP PM3: pathogenic-variant evidence in trans with the evaluated variant in an affected individual, with strength dependent on the number and quality of independent observations; phase and disease inheritance must be established.

Evidence considered

• The extracted report for PMID:15737014 describes T790M as an acquired mutation in progressing tumors and states that, in patients 1 and 2, T790M was inferred to be on the same EGFR allele as the pre-existing activating mutation; this is somatic cis evidence, not qualifying germline trans evidence for PM3.
• The extracted report for PMID:15728811 describes T790M in a recurrent gefitinib-resistant tumor and functional assays, without documenting a second pathogenic variant in trans in an affected germline proband.
• No EGFR-specific VCEP or CSPEC was present in the case bundle; the case therefore used generic ACMG/AMP fallback.

Still missing

• No affected-proband genotype containing a second pathogenic EGFR variant was provided.
• No parental testing, haplotyping, or other germline phase evidence establishing trans configuration was provided.
• The applicable germline disease inheritance model for this EGFR variant was not specified in an authoritative gene-specific framework.

Sources

Reasoning

The case evidence does not document an established pathogenic missense variant at EGFR residue 790 that is an alternate amino-acid substitution. The precomputed PM5 candidate summary contains zero same-residue candidates and explicitly states that classic PM5 semantics could not be confirmed safely. The exact T790M literature does not substitute for evidence about an alternate change at the same residue.

Rule

Generic ACMG/AMP PM5 requires a different pathogenic missense change at the same residue; evidence about the assessed substitution itself is insufficient.

Evidence considered

• The PM5 candidate summary reports zero total candidates and zero same-residue candidates, and instructs that PM5 should not be applied from that artifact alone.
• The available literature concerns the T790M substitution itself and does not establish an alternate pathogenic missense change at residue 790.

Still missing

• No validated pathogenic alternate missense variant at residue 790 was identified in the case evidence.
• A systematic same-residue ClinVar/pathogenicity comparison is not available in the bundle.

Sources

Reasoning

No presumed de novo occurrence is documented without parental testing. The bundle provides no family history, parental availability or genotype, maternity/paternity information, or clinical basis for a presumed de novo event. Therefore PM6 cannot be assessed.

Rule

Generic ACMG/AMP PM6: presumed de novo occurrence in a patient with the disease and no family history when maternity and paternity are unconfirmed or parental testing is unavailable; this is weaker than PS2 and still requires a documented clinical case context.

Evidence considered

• The case-evidence bundle contains no parental testing or family-history information for EGFR NM_005228.5:c.2369C>T (p.Thr790Met).
• The extracted literature describes acquired somatic T790M in tumors, not a presumed germline de novo occurrence.

Still missing

• Evidence that the variant is absent from available tested parents or that parental testing was unavailable
• Documented negative family history and relevant phenotype in the proband
• Maternity/paternity confirmation or other relationship evidence
• Clinical report supporting presumed de novo status

Reasoning

No informative relatives, family pedigree, variant-positive affected relatives, variant-negative unaffected relatives, meioses, or segregation counts are reported. Phenotype consistency across relatives therefore cannot be evaluated, and PP1 cannot be assessed.

Rule

Generic ACMG/AMP PP1: cosegregation with disease in multiple affected family members in a gene known to cause the disease; strength depends on the number and informativeness of meioses and the specificity/consistency of the phenotype.

Evidence considered

• The case-evidence bundle contains no pedigree, familial testing results, segregation analysis, or meiosis count for this variant.
• The extracted publications report tumor acquisition and drug resistance, not cosegregation of a germline variant with a phenotype.

Still missing

• Pedigree with affected and unaffected relatives
• Genotypes and phenotypes for informative relatives
• Number of informative meioses and segregation observations
• Assessment of phenotype specificity and consistency

Reasoning

The available evidence establishes EGFR missense changes as important somatic oncogenic and drug-response events, but it does not establish an applicable germline EGFR disease mechanism in which missense variants are a common pathogenic mechanism while benign missense variation is rare. Therefore PP2 cannot be applied from the available case bundle.

Rule

Generic ACMG/AMP PP2 requires a gene in which missense variants are a common disease mechanism and benign missense variation is uncommon; both gene-level conditions must be established for the relevant disease context.

Evidence considered

• The case has no applicable EGFR CSPEC/VCEP framework and falls back to generic ACMG.
• The available EGFR publications describe somatic lung-cancer biology and TKI resistance, which do not by themselves establish the generic germline PP2 gene-level assumptions.

Still missing

• No applicable EGFR-specific germline framework defining a missense-driven disease mechanism was available.
• No comprehensive benign missense variation analysis and disease-relevant missense enrichment assessment were provided.

Reasoning

No individual-level phenotype, pedigree, or testing context is supplied for this case. The available tumor-treatment evidence does not establish that the presenting phenotype in this case is highly specific for a germline EGFR-related disorder.

Rule

Generic ACMG/AMP PP4 requires a patient phenotype or family history highly specific for a disease with a single genetic etiology.

Evidence considered

• The consolidated bundle contains no case-level phenotype or pedigree for the individual being classified.

Still missing

• Case-level phenotype, age at onset, tumor and germline testing context, and family history are required.
• Evidence that the documented phenotype is sufficiently specific for an EGFR-related germline condition is required.

Reasoning

No well-established functional study in the available case evidence demonstrates that EGFR T790M has no damaging effect or normal functional activity. The available functional studies instead report altered kinase activity and inhibitor resistance, which are relevant to PS3 and cannot support BS3.

Rule

Generic ACMG/AMP BS3: well-established functional studies showing no damaging effect. No qualifying benign functional result was available.

Evidence considered

• The reviewed functional studies consistently evaluated altered EGFR signaling, kinase activity, or tyrosine-kinase-inhibitor response and did not provide evidence of a normal/benign functional effect for the exact variant.

Still missing

• A validated assay showing normal EGFR function for the exact variant, with appropriate positive and negative controls and a disease-relevant endpoint, is not available.

Reasoning

No affected or unaffected relatives with documented genotype and phenotype are provided. Consequently, there is no reliable evidence that the variant fails to segregate with disease, and BS4 cannot be assessed.

Rule

Generic ACMG/AMP BS4: lack of segregation in affected members of a family; application requires informative relatives and consideration of phenocopies, reduced age-related penetrance, and phenotype specificity.

Evidence considered

• The case-evidence bundle provides no family segregation or non-segregation observations for EGFR NM_005228.5:c.2369C>T (p.Thr790Met).
• The available literature extractions do not report familial non-segregation evidence for this variant.

Still missing

• Pedigree and disease-status information for relatives
• Variant testing results in affected relatives
• Variant testing results in unaffected relatives
• Consideration of age-related penetrance, phenocopies, and phenotype specificity

Reasoning

The case evidence does not establish that EGFR disease is predominantly caused by truncating or other non-missense variants in an applicable germline disease context. Somatic EGFR T790M oncogenic and drug-resistance observations cannot be used to infer BP1. Accordingly, BP1 is not assessed.

Rule

Generic ACMG/AMP BP1 requires a gene in which pathogenic variants are predominantly truncating or otherwise non-missense; this gene-level condition must be established for the relevant disease context.

Evidence considered

• The available framework materials contain no applicable EGFR CSPEC/VCEP specification.
• The available papers concern somatic EGFR kinase-domain mutations and treatment resistance rather than a validated germline disease variant spectrum.

Still missing

• No applicable EGFR-specific germline framework or disease-level variant-spectrum analysis was available.
• No reliable comparison showing predominance of truncating/non-missense pathogenic variants over missense variants was provided.

Reasoning

The case evidence does not document a qualifying germline observation of EGFR c.2369C>T in trans with a pathogenic variant or in cis with a pathogenic variant under the applicable dominant/recessive context. The extracted literature reports T790M in somatic tumors and describes cis occurrence with pre-existing activating EGFR mutations during acquired drug resistance; that tumor phase observation is not sufficient to apply BP2 to this germline variant assessment.

Rule

Generic ACMG/AMP BP2: observation of the evaluated variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant for a recessive disorder, provided the phase, disease context, and pathogenicity of the comparator are established.

Evidence considered

• The extracted report for PMID:15737014 states that T790M was inferred to be on the same allele as L858R or an exon 19 deletion in tumor material and in the H1975 cell line; this is somatic cis resistance biology and does not establish a qualifying germline BP2 observation.
• No qualifying germline trans or cis observation with a second established pathogenic variant was found in the consolidated case-evidence bundle.

Still missing

• No germline genotype or family-based phase result involving c.2369C>T and another pathogenic variant was provided.
• No evidence establishes that any observed second variant meets the pathogenic-variant requirement for BP2.
• No authoritative EGFR disease-specific rule defining the relevant BP2 phase context was available.

Sources

Reasoning

No case-level evidence identifies an alternative molecular diagnosis that fully explains the individual's phenotype.

Rule

Generic ACMG/AMP BP5 requires a variant in a gene for which another molecular basis for disease has been found in the individual.

Evidence considered

• The consolidated bundle contains no alternate molecular diagnosis or patient-specific phenotype attribution.

Still missing

• Case-level phenotype and results of testing for alternative molecular diagnoses are required.