EGFR c.2155G>A, p.Gly719Ser

Reasoning

PS3 is met at strong strength. PMID:16187797 directly studied EGFR p.G719S (c.2155G>A) using multiple orthogonal functional systems: anchorage-independent growth and focus formation in NIH-3T3 and hTBE cells, constitutive EGFR/STAT3/Akt signaling, inhibition by erlotinib and gefitinib, and tumor formation in immunocompromised mice. The exact variant induced oncogenic transformation without exogenous EGF and increased anchorage-independent growth approximately 15-fold over wild-type or control cells. These concordant cellular, biochemical, pharmacologic, and in vivo results are well-established functional evidence supportive of a damaging effect on EGFR function. The study was not described as a validated clinical diagnostic laboratory assay, so no evidence beyond the generic PS3 strong category is assigned.

Rule

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.

Evidence considered

• Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants (PMID:16187797) directly tested EGFR p.G719S/c.2155G>A in NIH-3T3 and hTBE cells and in immunocompromised mice.
• The exact p.G719S variant induced anchorage-independent growth without exogenous EGF, increased anchorage-independent growth approximately 15-fold over wild-type or control cells, showed constitutive EGFR C-terminal phosphorylation and STAT3/Akt activation, and produced tumors in mice; transformation was inhibited by erlotinib and gefitinib.
• The evidence is concordant across cellular transformation, signaling, pharmacologic inhibition, and in vivo tumor-formation assays, but the source does not describe validation in a clinical diagnostic laboratory setting.

Sources

Reasoning

PM2 is met at supporting strength. The exact EGFR NM_005228.5:c.2155G>A (p.Gly719Ser) variant is absent from gnomAD v2.1 exomes, gnomAD v4.1, gnomAD v2.1 non-cancer exomes, gnomAD v3.1 non-cancer genomes, and gnomAD-Canada v1.0. Thus the observed allele frequency is zero in the available control datasets, which is below the generic supporting threshold of <=0.0001. No VCEP-specific population source is governing this interpretation, so the all-comers datasets are the default; the non-cancer subsets independently support the same absence finding.

Rule

PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)

Evidence considered

• gnomAD v2.1 exomes reports the exact variant as absent.
• gnomAD v4.1 reports the exact variant as absent.
• The case evidence reports the exact variant as absent from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes.
• gnomAD-Canada v1.0 reports the exact variant as absent.
• Observed allele frequency is therefore 0 in each available dataset; no filtering AF, grpmax FAF, or popmax point estimate is available because the variant was not found.
• Generic calibration supplied for this case: PM2 supporting threshold <=0.0001, identified as the ClinGen SVI recommendation to downgrade PM2 to Supporting (PMID:25741868).

Sources

Reasoning

The variant is a missense substitution, p.(Gly719Ser), so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for PP3/BP4 in this situation. REVEL is 0.853, meeting the generic PP3 moderate threshold of >= 0.773 (ClinGen SVI REVEL calibration, Pejaver et al. 2022, PMID:36413997).

Rule

PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (moderate): >= 0.773 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)

Evidence considered

• NM_005228.5:c.2155G>A is annotated as the missense variant NP_005219.2:p.(Gly719Ser), so REVEL is the applicable computational path.
• Local REVEL lookup reports score 0.853 for chr7:55174014 G>A.
• ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet; PMID:36413997) sets generic PP3 moderate at >= 0.773; 0.853 meets this threshold.
• SpliceAI max delta 0.019 and BayesDel 0.356918 were not counted because the generic rule requires one consequence-matched path and BayesDel has no generic ACMG-strength calibration.

Sources

Reasoning

PP5 requires a reputable source to recently report the variant as pathogenic when the evidence is unavailable to the laboratory for independent evaluation. ClinVar has no expert-panel submission for this exact variant; its Likely pathogenic assertion is a non-expert, no-criteria-provided somatic submission, which is expressly excluded by the instructions. OncoKB labels the variant Oncogenic, not a qualifying exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification. PP5 is not met.

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 16612 lists zero expert-panel submissions; the Likely pathogenic record is SCV004042726 from a laboratory submission with no assertion criteria provided and somatic origin.
• OncoKB reports a variant-specific Oncogenic label and gain-of-function context, not an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification.

Sources

Reasoning

BA1 is not met. The variant is absent from gnomAD v2.1 and gnomAD v4.1, so no allele-frequency value reaches the generic stand-alone threshold of >=0.05. The available evidence does not provide a population-specific point estimate or filtering allele frequency above threshold. The variant is also reported as a somatic EGFR oncogenic mutation, but that context does not create a benign population-frequency basis for BA1.

Rule

BA1: Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)

Evidence considered

• gnomAD v2.1 (exome) reports the exact variant as absent.
• gnomAD v4.1 reports the exact variant as absent.
• Generic calibration supplied for this case: BA1 stand-alone threshold >=0.05, attributed to ACMG/AMP 2015 (PMID:25741868).

Sources

Reasoning

BS1 is not met. The exact variant is absent from gnomAD v2.1, gnomAD v4.1, gnomAD v2.1 non-cancer, gnomAD v3.1 non-cancer, and gnomAD-Canada v1.0; therefore there is no observed filtering allele frequency or grpmax FAF greater than expected for the disorder. The generic 1% default is not reached. No maximum-credible-frequency calculation is needed because the observed frequency is zero in the available population datasets.

Rule

BS1: Allele frequency is greater than expected for the disorder. ... BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)

Evidence considered

• gnomAD v2.1 (exome) reports the exact variant as absent.
• gnomAD v4.1 reports the exact variant as absent.
• The case evidence also reports absence from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer; neither dataset provides an observed allele count, allele frequency, or grpmax FAF.
• gnomAD-Canada v1.0 reports the exact variant as absent.
• Because no frequency is observed, ancestry concentration, isolate-group sample size, and a maximum-credible-frequency calculation cannot produce a pathogenic-frequency exclusion here.
• Generic calibration supplied for this case: BS1 threshold >=0.01; per-gene derivation is preferred under Whiffin et al. 2017 (PMID:28518168).

Sources

Reasoning

BS3 is not met. The directly relevant functional study of EGFR p.G719S showed damaging gain-of-function phenotypes, including EGF-independent transformation, constitutive signaling, increased anchorage-independent growth, and tumor formation in immunocompromised mice. No well-established assay evidence showing no damaging effect on EGFR protein function or splicing was identified.

Rule

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

Evidence considered

• Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants (PMID:16187797) directly tested EGFR p.G719S/c.2155G>A and reported damaging gain-of-function phenotypes rather than a benign functional result.
• The study found EGF-independent transformation, constitutive EGFR/STAT3/Akt signaling, increased anchorage-independent growth, and tumor formation in immunocompromised mice; therefore it does not support BS3.

Still missing

• No well-established functional study demonstrating no damaging effect on EGFR protein function or splicing was identified.

Sources

Reasoning

The variant is a missense substitution, so BP4 must be judged from REVEL only; SpliceAI's low score cannot substitute for an indeterminate REVEL result. REVEL is 0.853, which is not <= 0.29, the generic BP4 supporting threshold, and therefore BP4 is not met. BayesDel is not applicable because no generic ACMG-strength calibration is established.

Rule

BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)

Evidence considered

• NM_005228.5:c.2155G>A is annotated as the missense variant NP_005219.2:p.(Gly719Ser), so REVEL is the applicable computational path.
• Local REVEL lookup reports score 0.853 for chr7:55174014 G>A; this is outside the BP4 gray-zone/benign threshold and does not meet BP4.
• ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet; PMID:36413997) sets generic BP4 supporting at <= 0.29; 0.853 does not meet this threshold.
• SpliceAI max delta 0.019 was not used for BP4 because a missense variant is adjudicated through the REVEL path only; BayesDel 0.356918 was not used because no generic ACMG-strength calibration is established.

Sources

Reasoning

BP6 requires a reputable source to recently report the variant as benign when the evidence is unavailable to the laboratory for independent evaluation. No exact-variant ClinVar expert-panel benign or likely benign classification is present; ClinVar instead reports uncertain significance, drug response, and non-expert likely pathogenic/likely oncogenic submissions. 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 16612 has no expert-panel submissions and does not report an exact-variant Benign or Likely benign expert-panel classification; the listed records are uncertain significance, drug response, Likely pathogenic, and Likely oncogenic.

Sources

Reasoning

The variant is NM_005228.5:c.2155G>A, p.Gly719Ser. The reviewed literature documents this exact EGFR missense variant in tumor cohorts and functional experiments, but no previously established pathogenic variant with the same amino-acid change and a different nucleotide change was identified. The available ClinVar entries are mixed somatic/drug-response or uncertain-significance records and do not establish the required pathogenic comparator. The evidence therefore does not establish PS1, and the specific gap is a confirmed pathogenic Gly719Ser comparator caused by another nucleotide change.

Rule

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

Evidence considered

• PMID:16187797 reports EGFR G719S in transformation and signaling assays, but it does not provide a different-nucleotide pathogenic comparator.
• PMID:16199108 reports the exact c.2155G>A/G719S variant in an NSCLC cohort, but does not establish a same-amino-acid comparator or germline pathogenic classification.
• PMID:23468066 reports the exact c.2155G>A/p.G719S variant in Table 3, case 10, but does not establish a different-nucleotide pathogenic comparator.
• ClinVar variation 16612 contains uncertain-significance, drug-response, and likely pathogenic somatic submissions, not a confirmed previously established pathogenic same-amino-acid comparator.

Still missing

• A previously established pathogenic Gly719Ser variant caused by a different nucleotide change is required.

Sources

Reasoning

No evidence establishes a germline de novo occurrence of NM_005228.5:c.2155G>A (p.Gly719Ser) in an affected proband. The available variant-specific reports describe somatic tumor specimens and provide no maternity confirmation, paternity confirmation, or documented absence of family history. Therefore, the PS2 requirements cannot be assessed.

Rule

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

Evidence considered

• PMID:16187797 reports experimental work on G719S and explicitly states that no patient-level segregation, population-frequency, or clinical case data for the exact variant were reported in the provided text.
• PMID:16199108 identifies G719S in an NSCLC tumor cohort but reports no segregation analysis or germline parental testing.
• PMID:23468066 reports c.2155G>A/p.G719S in a fine-needle aspiration NSCLC specimen, supporting a somatic tumor context rather than a documented germline de novo event.

Still missing

• Affected proband phenotype and diagnosis
• Germline variant testing in the proband
• Confirmed maternity
• Confirmed paternity
• Documented absence of family history

Sources

Reasoning

The governing ACMG/AMP rule requires that the prevalence of the variant in affected individuals be significantly increased compared with controls; its Note 1 specifies an RR or OR >5.0 with a confidence interval that does not include 1.0. The reviewed exact-variant papers document G719S in NSCLC cases or treated tumor samples, but do not provide a matched unaffected/population-control comparison or sufficient case and control counts to calculate an OR and 95% CI. Therefore, PS4 cannot be assessed from the available evidence; the absence of gnomAD observations is not a case-control comparison and does not supply the required affected-case prevalence.

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

• PMID:23468066, Results Table 3 case 10: EGFR c.2155G>A/p.G719S was detected in one micropapillary NSCLC tumor specimen at 39.5% allele frequency; no unaffected or population control comparison was reported.
• PMID:16199108, Tables 1-2 and Results: G719S was detected in sample 12 among 27 gefitinib-treated NSCLC samples; the paper did not provide a separate control frequency or case-control analysis.
• PMID:16187797, Results: G719S was studied in cellular and mouse transformation models, with no patient-level case-control data for the exact variant.
• PMID:18573086, structural review: the extracted passage is general EGFR mutation biology and does not provide exact-variant case-control data.
• gnomAD v2.1, v4.1, and gnomAD-Canada report the variant as absent, but those population observations alone do not establish affected-case prevalence or a calculable case-control OR for PS4.

Still missing

• A matched case-control study or usable affected-case and control counts/frequencies for EGFR c.2155G>A are needed to calculate OR/RR and its 95% CI.

Sources

Reasoning

p.Gly719Ser lies in the EGFR intracellular tyrosine-kinase domain, a biologically critical region, and Cancer Hotspots reports an EGFR G719 hotspot. However, the hotspot record is partially parsed, no VCEP governs EGFR, and the available evidence does not establish the required absence of benign variation for the relevant domain or hotspot. The generic PM1 evidence threshold is therefore not fully met from the available records.

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

• PMID:18573086 describes the EGFR intracellular tyrosine-kinase domain as the region containing cancer-associated EGFR-TK mutations and discusses its structural functional importance, but is not a benign-variation analysis.
• Cancer Hotspots reports a statistically significant EGFR G719 hotspot, but the record is explicitly marked as partially parsed and supplies no benign-variation data.

Still missing

• A reliable domain or hotspot assessment demonstrating absence of benign variation is required.
• The partially parsed Cancer Hotspots record requires independent verification if used.

Sources

Reasoning

PM3 cannot be assessed because the available evidence is somatic tumor evidence and does not establish a recessive disease context, an affected proband, a pathogenic second allele, or parental/offspring testing demonstrating that the variants are in trans. The exact variant was reported with EGFR c.2126A>C (p.E709A) in one tumor sample, but the report does not determine phase or establish the accompanying variant as pathogenic for a recessive disorder.

Rule

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

Evidence considered

• PMID:23468066, Results Table 3 case 10: EGFR c.2155G>A (p.G719S) was observed with EGFR c.2126A>C (p.E709A) in an 81-year-old female's NSCLC tumor, with 39.5% allele frequency; the report provides no germline inheritance or phase determination and does not establish p.E709A as pathogenic.
• PMID:16199108, Tables 1–2: EGFR G719S was identified in a gefitinib-treated NSCLC tumor sample; this is somatic tumor evidence without parental testing, affected-proband segregation, or trans-phase evidence.

Still missing

• A confirmed recessive EGFR-associated disorder context is not established.
• No affected-proband germline observation is documented.
• No pathogenic allele in the same individual is documented.
• No parental or offspring testing establishes trans phase.

Sources

Reasoning

The target residue is Gly719. The reviewed evidence documents Gly719Ser itself, but the case materials contain no confirmed different missense substitution at Gly719 that was determined to be pathogenic. The PM5 candidate artifact reports zero same-residue candidates and explicitly cannot confirm classic PM5 semantics. A confirmed pathogenic alternate missense change at Gly719 is therefore the unresolved requirement.

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 candidate record reports zero same-residue candidates and states that classic PM5 semantics could not be confirmed.
• The reviewed publications report Gly719Ser but do not establish a different pathogenic missense substitution at Gly719.
• ClinVar variation 16612 is the exact Gly719Ser record and does not provide a confirmed pathogenic alternate missense change at Gly719.

Still missing

• A different missense variant at Gly719 with a confirmed pathogenic classification is required.

Sources

Reasoning

No evidence establishes an assumed germline de novo occurrence of NM_005228.5:c.2155G>A (p.Gly719Ser). The available reports are based on somatic tumor specimens and do not document a proband with the disease plus unconfirmed parental testing or a family-history assessment. Therefore, PM6 cannot be assessed.

Rule

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

Evidence considered

• PMID:16187797 reports no patient-level segregation or clinical case data for exact G719S in the provided text.
• PMID:16199108 reports G719S in a tumor cohort and does not provide parental testing or germline de novo evidence.
• PMID:23468066 reports G719S in a fine-needle aspiration NSCLC specimen, without parental or family segregation data.

Still missing

• Affected proband phenotype and diagnosis
• Germline variant testing in the proband
• Parental testing or documented parental status
• Family-history assessment

Sources

Reasoning

No affected family members, informative meioses, genotype results, or phenotype-consistent segregation observations are reported for NM_005228.5:c.2155G>A (p.Gly719Ser). The available literature describes tumor cohorts or functional studies rather than familial segregation. Therefore, PP1 cannot be assessed or strengthened.

Rule

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

Evidence considered

• PMID:16187797 is a functional study and reports no patient-level segregation or clinical case data for G719S.
• PMID:16199108 is a tumor-cohort assay study and provides no familial segregation information for G719S.
• PMID:23468066 reports G719S in a somatic NSCLC specimen and provides no affected-relative genotypes or meioses.

Still missing

• Pedigree and affected-relative information
• Genotypes of affected relatives
• Phenotype consistency among relatives
• Number of informative meioses

Sources

Reasoning

EGFR missense variants are a common mechanism in somatic cancer and p.Gly719Ser has variant-specific gain-of-function evidence, but PP2 requires a gene-level low rate of benign missense variation together with missense as a common disease mechanism. The case materials do not provide a validated gene-level benign-missense rate or an appropriate germline disease-mechanism assessment for EGFR. PP2 is consequently not assessed.

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

• PMID:16187797 provides exact-variant gain-of-function evidence for G719S, but does not quantify the gene-level rate of benign missense variation.
• OncoKB labels the somatic G719S context as gain-of-function/oncogenic, which is not by itself the gene-level germline evidence required for PP2.
• PMID:18573086 provides general EGFR structural and mutation-mechanism context, but not a validated benign-missense rate.

Still missing

• A validated gene-level assessment showing a low rate of benign missense variation is required.
• The relevant disease context and evidence that missense is a common mechanism must be established for the applicable EGFR disorder.

Sources

Reasoning

The governing rule requires a patient's phenotype or family history highly specific for a disease with a single genetic etiology. The available evidence identifies the variant in somatic NSCLC tumor cohorts and functional models, but supplies no germline patient phenotype or family-history description that is highly specific for a single-gene disease. PP4 therefore cannot be assessed.

Rule

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

Evidence considered

• PMID:23468066 reports p.G719S in an 81-year-old female's micropapillary NSCLC tumor specimen, but does not establish a highly specific inherited phenotype or family history.
• PMID:16199108 reports G719S among gefitinib-treated NSCLC tumor samples; this is a tumor-treatment context rather than a specific germline phenotype/family-history presentation.

Still missing

• A documented patient phenotype or family history highly specific for a disease with a single genetic etiology is needed.

Sources

Reasoning

BS2 is not assessed. The available evidence contains no observation of this variant in a healthy adult individual as a germline heterozygote, homozygote, or X-linked hemizygote. The literature entries concern somatic EGFR mutations in cancer specimens and do not establish a healthy-adult germline observation. A BS2 judgment would additionally require a defined disorder and the assumption that full penetrance is expected at an early age; those disease/inheritance parameters are not established for this EGFR somatic oncogenic variant.

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 v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 report absence rather than a healthy-adult carrier or homozygote observation.
• The extracted literature observations are from NSCLC tumor specimens and describe somatic EGFR G719S; they are not healthy-adult germline observations.
• No evidence establishes the BS2-required disorder, inheritance mode, and full early-age penetrance assumptions for this variant.

Still missing

• A verified healthy-adult germline observation for the exact variant is unavailable.
• A defined germline EGFR disorder with inheritance and early-age full-penetrance expectations is unavailable for this variant context.

Sources

Reasoning

No family with affected members carrying or lacking NM_005228.5:c.2155G>A (p.Gly719Ser) is described. Consequently, there are no affected-member genotype/phenotype comparisons from which lack of segregation can be established, and BS4 cannot be assessed.

Rule

Lack of segregation in affected members of a family.

Evidence considered

• PMID:16187797 reports no patient-level segregation or clinical case data for G719S.
• PMID:16199108 reports G719S in tumor samples without affected-family genotype comparisons.
• PMID:23468066 reports G719S in a tumor specimen without family-based genotype/phenotype data.

Still missing

• Pedigree and affected-relative information
• Genotypes of affected relatives
• Phenotype assessments for affected relatives
• Evidence that the variant is absent in affected relatives

Sources

Reasoning

The variant is missense, so BP1 is applicable in principle. The case materials do not establish that EGFR-related disease is caused primarily by truncating variants, nor do they provide a disease-specific comparison demonstrating that missense variants are unusual. The available EGFR literature instead concerns somatic activating missense mutations and cannot establish the BP1 gene-level pattern.

Rule

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

Evidence considered

• PMID:16187797 documents activating EGFR missense mutations in cancer and therefore does not establish a primarily truncating disease mechanism.
• PMID:18573086 discusses EGFR kinase-domain mutations generally but does not provide a disease-specific truncating-versus-missense variant spectrum.
• OncoKB describes the variant-specific somatic context as gain-of-function/oncogenic, not the primarily truncating pattern required for BP1.

Still missing

• A disease-specific variant-spectrum analysis showing primarily truncating pathogenic variants is required.

Sources

Reasoning

BP2 cannot be assessed because no pathogenic variant in the same individual is documented in trans or cis. The available reports describe EGFR c.2155G>A in somatic lung-cancer samples, including one sample with EGFR c.2126A>C (p.E709A), but provide neither phase information nor evidence that the accompanying variant is pathogenic. The case therefore does not establish either required BP2 configuration.

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:23468066, Results Table 3 case 10: p.G719S was listed with EGFR p.E709A in the same tumor specimen, but the study did not determine cis/trans phase or classify p.E709A as pathogenic.
• PMID:16199108, Tables 1–2: the target variant was reported in a somatic NSCLC sample, without a pathogenic paired variant or phase analysis.

Still missing

• No pathogenic variant paired with the target variant is documented.
• No cis or trans phase determination is available.
• No germline affected-proband or family-based observation is documented.

Sources

Reasoning

BP5 requires the variant to be found in a case with an alternate molecular basis for disease. The reviewed exact-variant reports describe EGFR G719S in NSCLC tumors, including co-occurring EGFR p.E709A in one specimen, but do not establish that an alternate molecular basis caused that patient's disease or provide the required case-level adjudication. BP5 cannot be assessed from the available evidence.

Rule

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

Evidence considered

• PMID:23468066, Results Table 3 case 10: p.G719S co-occurred with EGFR p.E709A in an NSCLC tumor specimen, but the paper does not adjudicate p.E709A as an alternate molecular basis for the disease.

Still missing

• A case report must document an alternate molecular basis for the disease and support that it explains the phenotype independently of EGFR c.2155G>A.

Sources