MET c.1063G>A, p.(Glu355Lys)

Reasoning

No governing VCEP/gene-specific PP3/BP4 lookup exists for MET (cspec.found=false; generic_acmg_fallback framework), so generic ACMG in-silico evidence applies. SpliceAI predicts essentially no splice impact for this variant: max delta score = 0.001 (DS_AG=0.0, DS_AL=0.0, DS_DG=0.001, DS_DL=0.0), far below the commonly applied SpliceAI 'no impact' threshold used in ACMG/AMP splice adjudication (delta scores well under 0.1, per the SpliceAI validation publication, Jaganathan et al. 2019, PMID 30661751). This supports BP4 (in-silico evidence suggests no splicing effect). The missense/REVEL path does not independently contribute to BP4: REVEL 0.31 sits in the indeterminate zone above the SVI-calibrated BP4-supporting cutoff of <=0.290 (PMID 36413997), so it neither adds to nor conflicts with the BP4 call from the splice-impact path. BayesDel is excluded per policy for lack of a citable calibrated threshold. Only the SpliceAI splice-impact line of evidence is used to avoid double counting across sub-paths.

Rule

generic_acmg_fallback: no gene-specific VCEP PP3/BP4 spreadsheet or lookup for MET was found; applied calibrated SpliceAI near-zero delta score as generic ACMG BP4 (supporting) evidence for absence of predicted splicing impact.

Evidence considered

• SpliceAI raw scores: DS_AG=0.0, DS_AL=0.0, DS_DG=0.001, DS_DL=0.0, max_delta_score=0.001; evidence_sentence 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).' (prefetch.json/evidence.json spliceai block). SpliceAI delta scores this far below 0.1 are interpreted as no predicted splicing effect per the original SpliceAI validation study (Jaganathan et al., Cell 2019, PMID 30661751), supporting BP4 at supporting strength.

Sources

Reasoning

PM2 is not met because the variant is present in population databases. gnomAD v4.1 identifies 60 alleles and gnomAD v2.1 identifies 7 alleles; although rare, the variant is not absent from controls. Its absence from gnomAD-Canada does not override its documented presence in the larger gnomAD datasets.

Rule

Generic PM2: variant absent or extremely rare in population databases appropriate to the disorder; presence of the variant in gnomAD prevents application of PM2 under this assessment.

Evidence considered

• gnomAD v4.1: 60/1,596,674 alleles, AF 3.75781e-05, zero homozygotes.
• gnomAD v2.1: 7/234,450 alleles, AF 2.98571e-05, zero homozygotes.
• gnomAD-Canada v1.0 reports the variant as absent, but absence in that dataset cannot support PM2 when the variant is observed in gnomAD v2.1 and v4.1.

Sources

Reasoning

No governing VCEP/gene-specific PP3/BP4 lookup exists for MET (cspec.found=false; final_classification_framework source=generic_acmg_fallback), so generic ACMG in-silico evidence applies. Splice path: SpliceAI predicts no splice impact (max delta score = 0.001, effectively zero across DS_AG/AL/DG/DL), which does not support PP3. Missense path: REVEL score is 0.31, which falls in the indeterminate zone between the ClinGen SVI-calibrated BP4-supporting cutoff (<=0.290) and PP3-supporting cutoff (>=0.644) from the REVEL recalibration study, so it does not reach the pathogenic-supporting threshold. BayesDel score (-0.169214) is present in the data but this pipeline has no verified published threshold/table citation for BayesDel, so per policy it is treated as not_available for PP3/BP4 regardless of the numeric value. No aGVGD or other missense in-silico tool result was found in the case bundle. No line of calibrated computational evidence meets a PP3 threshold.

Rule

generic_acmg_fallback: no gene-specific VCEP PP3/BP4 spreadsheet or lookup for MET was found; applied calibrated computational thresholds (SpliceAI splice-impact path; REVEL missense path with SVI-calibrated cutoffs) since no VCEP override exists.

Evidence considered

• SpliceAI evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).' with raw scores DS_AG=0.0, DS_AL=0.0, DS_DG=0.001, DS_DL=0.0 (prefetch.json/evidence.json spliceai block).
• REVEL score = 0.31 (prefetch.json/evidence.json revel block), which is below the ClinGen SVI PP3-supporting REVEL threshold (>=0.644) per the published REVEL recalibration for ACMG/AMP use (PMID 36413997), so REVEL does not support PP3.
• BayesDel score -0.169214 is present (prefetch.json/evidence.json bayesdel block) but has no verified published PP3/BP4 threshold citation available to this pipeline, so it is excluded from this determination per policy.

Still missing

• No verified/citable BayesDel threshold publication available to this pipeline, so the BayesDel score cannot be used for PP3 despite being present in the data.
• No aGVGD or additional missense in-silico predictor score found in the case bundle.

Sources

Reasoning

BA1 is not met. The variant frequency is far below the generic benign stand-alone threshold: gnomAD v4.1 reports 60/1,596,674 alleles (AF 3.75781e-05; 0.00376%), with the highest broad population AF in African/African American individuals at 7/74,242 (9.42863e-05; 0.00943%).

Rule

Generic BA1: apply only when the allele frequency is sufficiently common for a stand-alone benign call; operational threshold used here is AF >1%.

Evidence considered

• gnomAD v4.1: total AF 3.75781e-05 (60/1,596,674 alleles), maximum broad population AF 9.42863e-05 in African/African American individuals, and zero homozygotes; these values are well below the generic BA1 threshold of 1%.
• gnomAD v2.1 independently reports AF 2.98571e-05 (7/234,450 alleles), maximum broad population AF 1.31199e-04, and zero homozygotes; these values are also well below 1%.
• No applicable MET-specific VCEP/CSPEC framework was available; generic ACMG/AMP population thresholds were therefore used.

Sources

Reasoning

BS1 is not met. The observed population frequency is not greater than the expected disease-associated frequency threshold. gnomAD v4.1 reports AF 3.75781e-05 overall and a maximum broad population AF of 9.42863e-05; both are far below the operational generic BS1 threshold of 0.3%.

Rule

Generic BS1: allele frequency is greater than expected for the disorder; operational threshold used here is AF >0.3% in the overall or relevant population.

Evidence considered

• gnomAD v4.1 reports 60/1,596,674 alleles (AF 3.75781e-05; 0.00376%) and a maximum broad population AF of 7/74,242 (9.42863e-05; 0.00943%) in African/African American individuals, with zero homozygotes.
• gnomAD v2.1 reports 7/234,450 alleles (AF 2.98571e-05; 0.00299%) and a maximum broad population AF of 2/15,244 (1.31199e-04; 0.01312%), with zero homozygotes.
• No applicable MET-specific VCEP/CSPEC framework was available; the generic operational BS1 threshold of AF >0.3% was used.

Sources

Reasoning

BP1 (missense variant in a gene for which primarily truncating variants are known to cause disease) does not apply to MET. MET's best-established germline disease mechanism is activating (gain-of-function) missense substitution in the tyrosine kinase domain causing dominant hereditary papillary renal cell carcinoma; missense variants are also the mechanism reported for the semaphorin/juxtamembrane domain substitutions studied in PMID:19723643. Since MET is not a gene where disease is primarily caused by truncating variants, the premise of BP1 fails and the criterion is not met (not applicable to invoke as benign evidence here).

Evidence considered

• PMID:19723643 states that identification of activating germline mutations of MET in hereditary papillary renal carcinoma provided the first direct evidence linking MET to human oncogenesis, and that MET mutations are missense/nonsynonymous substitutions (not truncating) clustered in the semaphorin, juxtamembrane, and tyrosine kinase domains, establishing missense (not truncating) as the principal disease-causing mechanism for MET-related dominant cancer phenotypes.

Sources

Reasoning

No CSPEC/VCEP framework exists for MET (framework_mode=generic_acmg, cspec.found=false); generic ACMG PS1 requires a different nucleotide change resulting in the identical amino acid change (p.Glu355Lys) with an established pathogenic classification. No such comparator was identified in ClinVar, the cited literature, or pm5_candidates.json (which explicitly did not run same-residue candidate harvesting for this variant). The ClinVar record for this exact variant (VCV000219769) itself shows conflicting Uncertain significance/Likely benign submissions, not an independent pathogenic determination for the same amino acid change, so it cannot be used as a PS1 comparator.

Evidence considered

• ClinVar VCV000219769 for NM_001127500.3:c.1063G>A (p.Glu355Lys) shows conflicting submissions (5 labs Uncertain significance, 3 labs Likely benign) and is not itself a comparator establishing pathogenicity for this exact amino acid change.
• pm5_candidates.json reports pm5_mode=unknown and eligible_for_classic_pm5_search=false, with zero candidates harvested, so no same-residue comparator data (which would also cover alternate-codon-same-amino-acid PS1 scenarios) is available in this case bundle.

Still missing

• No search was performed for other codon changes at position 355 that also yield p.Glu355Lys with an established pathogenic classification
• pm5_candidates.json explicitly skipped automated same-residue harvesting (eligible_for_classic_pm5_search=false)

Sources

Reasoning

No case-specific evidence documents a confirmed de novo occurrence of NM_001127500.3:c.1063G>A (p.Glu355Lys) in a proband with validated maternity and paternity or parental genotypes.

Rule

Generic ACMG/AMP PS2 requires a confirmed de novo variant in a patient with the relevant phenotype, with maternity and paternity confirmed; stronger application requires additional well-established de novo observations and/or phenotype specificity.

Evidence considered

• The consolidated case-evidence bundle contains no case-specific proband, parental-testing, de novo, or maternity/paternity evidence for this variant.
• ClinVar records variant submissions and classifications but does not provide usable case-level parental testing or confirmed de novo data in the supplied evidence.

Still missing

• Proband phenotype and diagnostic context are not documented in the case-evidence bundle.
• Parental testing results and confirmation of maternity and paternity are not documented.
• The number of tested probands, testing methodology, and any mosaicism assessment are not documented.

Reasoning

No ClinGen VCEP specification is available for MET (framework_mode: generic_acmg_fallback, cspec.found=false), so generic ACMG/AMP PS3 requirements apply. No validated functional assay (e.g., kinase autophosphorylation, transformation/colony-formation, HGF-independent signaling, mouse xenograft) targeting this specific variant (NM_001127500.3:c.1063G>A, p.Glu355Lys / isoform-2 numbering p.Glu373Lys) was found in the case bundle. OncoKB has no variant-specific reviewed functional evidence (classification: Unknown Oncogenic Effect, is_variant_specific=false). PMID 21904579 (functional-theme paper) only lists E355K in a table of MET mutations observed across tumor types/domains without reporting any assay result, controls, or biological readout for this variant. PMID 19723643 (functional theme, ClinVar-cited) does not mention this variant/residue anywhere in full text. No other source in the bundle (prefetch, evidence.json, literature_pass, vcep_materials) supplies assay data for this variant.

Evidence considered

• OncoKB (oncokb source) queried for MET/E355K: 'not_reviewed': true, 'is_variant_specific': false, classification 'Unknown Oncogenic Effect', with only gene-level summary text.
• PMID 21904579 full text: E355K appears only as a row in Table 2, a compilation list of MET mutations by domain (SEMA) and tumor type, with no assay description, functional readout, or controls reported for this specific variant.
• Full-text search of PMID 19723643 (labeled 'functional' theme in source_registry) found zero occurrences of residue 355 or the variant anywhere in the paper.

Still missing

• No validated in vitro or in vivo functional assay (kinase activity, transformation, proliferation, xenograft) specific to p.Glu355Lys/p.Glu373Lys was located in the retrieved literature.
• OncoKB lists this variant with no reviewed variant-specific functional annotation.
• PMID 21904579's mutation table entry for E355K has no accompanying experimental methodology, controls, or quantitative readout to assess assay validity or biological relevance.

Sources

Reasoning

No variant-specific affected-case versus control comparison, enrichment statistic, or adequately documented series of affected individuals was available for NM_001127500.3:c.1063G>A (p.Glu355Lys). The reviewed cancer referral guidelines are not variant-specific case-control evidence.

Rule

Generic ACMG/AMP PS4: prevalence of the variant in affected individuals is significantly increased compared with controls; apply only with variant-specific, interpretable case-control or equivalent phenotype-enrichment evidence.

Evidence considered

• The case bundle identifies no MET-specific VCEP/CSPEC; generic ACMG/AMP fallback therefore applies.
• ClinVar contains only ordinary single-submitter laboratory assertions for this exact variant and no expert-panel submission; these assertions are not PS4 evidence.
• COSMIC reports the exact variant in four somatic cancers, but this is not a germline affected-case versus control enrichment analysis and does not establish PS4.
• The reviewed hereditary renal-cell-cancer and cancer-genetics referral publications provide clinical referral criteria, not variant-specific PS4 case-control data.

Still missing

• Variant-specific case-control or statistically interpretable affected-case enrichment data are unavailable.
• A variant-specific phenotype series with reliable denominators and an appropriate disease definition is unavailable.

Sources

Reasoning

No CSPEC/VCEP framework exists for MET, so generic ACMG PM1 (mutational hotspot or well-established functional domain without benign variation) applies. p.Glu355Lys falls within the MET semaphorin (Sema) extracellular domain, which functional literature (PMID:19723643) identifies as the ligand (HGF)-binding region and a cluster site for germline nonsynonymous MET substitutions in lung cancer cohorts (e.g., N375S, E168D, L211W). However, that same paper also documents that the semaphorin domain tolerates multiple synonymous and nonsynonymous polymorphisms (e.g., S178, I377 synonymous SNPs; N375S itself listed in dbSNP as a common polymorphism), arguing against 'low rate of benign missense variation' for this domain overall. Cancerhotspots.org returned no significant hotspot at MET E355 (evidence.json: search_status=no_result). No residue-specific structural/functional data (e.g., direct HGF contact residue) was found for E355 itself (only E168 and L229 are reported as direct HGF-contact residues in the crystal structure model). This is insufficient to establish PM1 for this specific residue.

Evidence considered

• PMID:19723643 (Krishnaswamy et al., Clin Cancer Res 2009) reports that nonsynonymous MET mutations detected in their lung cancer cohorts clustered in the semaphorin domain (except one juxtamembrane R988C), and that the semaphorin domain harbors the HGF ligand-binding site; molecular modeling identified E168 and L229 as residues in direct contact with HGF, but E355 was not identified as a direct contact residue.
• The same paper also reports several benign/common polymorphisms within the semaphorin domain (synonymous S178, I377 substitutions; N375S is a frequent, apparently tolerated polymorphism enriched in East Asian populations), indicating the domain is not free of benign missense variation.
• hotspots (cancerhotspots.org) search for 'MET E355' returned no_result / not a statistically significant hotspot (screenshots/hotspots.png; evidence.json).

Still missing

• No cancerhotspots.org, COSMIC, or curated mutational-cluster data specific to codon 355
• No structural evidence that E355 itself directly contacts HGF or another critical functional site (only E168/L229 were identified as direct contact residues)
• Semaphorin domain overall shows tolerance to benign/polymorphic missense and synonymous variation, weakening a domain-wide PM1 argument

Sources

Reasoning

No applicable MET-specific VCEP/CSPEC framework was retrieved, so the generic ACMG/AMP framework was used. The case bundle contains no affected-proband observations, second pathogenic or likely pathogenic variant, phase information, compound-heterozygous observation, or inheritance data demonstrating this variant in trans with a pathogenic variant for a recessive condition. PM3 therefore cannot be assessed.

Rule

Generic ACMG/AMP PM3 requires well-established pathogenic or likely pathogenic variants in trans in affected individuals with a recessive disorder; phase and disease context must support the observation.

Evidence considered

• The case bundle identifies MET and reports no retrieved CSPEC/VCEP framework.
• The case bundle provides ClinVar submissions and population/predictor data but no family-level or allelic observations relevant to PM3.

Still missing

• Affected-proband genotype and phenotype data are absent.
• No pathogenic or likely pathogenic partner variant is documented.
• No parental testing or other phase evidence establishes trans or cis configuration.
• The relevant inheritance mode for the reported condition is not established in the case evidence.

Reasoning

pm5_candidates.json explicitly declined to run classic same-residue PM5 candidate harvesting for this variant (pm5_mode=unknown, eligible_for_classic_pm5_search=false, candidate_summary all zero), with the recommendation to not apply PM5 from this artifact alone. No other source in the bundle (ClinVar record, literature) identifies an alternate missense change at codon 355 (e.g., p.Glu355Asp, p.Glu355Gly, p.Glu355Val, etc.) with an established pathogenic/likely pathogenic classification. Without that comparator data, PM5 cannot be assessed as met.

Evidence considered

• pm5_candidates.json for this case reports 'Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting' with zero same-residue candidates collected, and explicitly instructs not to apply PM5 from this artifact alone.

Still missing

• No ClinVar or literature search was completed for alternate amino-acid substitutions at MET codon 355
• pm5_candidates.json artifact itself flags this as an unresolved data gap requiring manual review

Sources

Reasoning

No case-specific evidence documents a suspected de novo occurrence without confirmed parental relationships for this variant.

Rule

Generic ACMG/AMP PM6 is applicable to a suspected de novo occurrence when parental relationships or parental testing are insufficiently confirmed; the supplied case must still document the relevant proband observation and suspected de novo context.

Evidence considered

• The consolidated case-evidence bundle contains no report of a suspected de novo event for NM_001127500.3:c.1063G>A (p.Glu355Lys).
• The supplied ClinVar and literature materials do not provide a case-level parental relationship or de novo observation that can support PM6.

Still missing

• No proband-level observation is described.
• No parental genotypes or testing methodology are described.
• No information is available to distinguish suspected de novo occurrence from an inherited variant or parental mosaicism.

Reasoning

No affected relatives, informative meioses, genotype-phenotype concordance, or other family segregation observations are provided for this variant.

Rule

Generic ACMG/AMP PP1 requires cosegregation with disease in affected family members; strength depends on the number and informativeness of meioses and the specificity of the phenotype.

Evidence considered

• The consolidated case-evidence bundle contains no family-level segregation data for NM_001127500.3:c.1063G>A (p.Glu355Lys).
• The literature triage supplied with the case does not identify a variant-specific family study reporting segregation for this variant.

Still missing

• No pedigree or family structure is documented.
• No affected-relative genotypes or segregation results are documented.
• No phenotype consistency assessment or count of informative meioses is available.

Reasoning

No CSPEC/VCEP framework exists for MET, so generic ACMG PP2 (missense variant in a gene where missense variants are a common mechanism of disease and there is a low rate of benign missense variation) would apply if supportable. MET disease mechanisms are mixed and domain-dependent: activating (gain-of-function) missense variants in the tyrosine kinase domain cause dominant hereditary papillary renal cell carcinoma, while MET-related hearing loss (also listed among this variant's ClinVar-associated conditions) is an autosomal recessive loss-of-function mechanism, and the semaphorin domain (where this variant lies) is documented in PMID:19723643 to tolerate multiple benign/polymorphic missense and synonymous changes. No gnomAD missense constraint metric (e.g., missense Z-score/o:e ratio) or formal statement of 'low rate of benign missense variation' for MET was present anywhere in the evidence bundle. Given the conflicting mechanism evidence and absence of a missense-tolerance metric, this cannot be reliably assessed as met or not_met.

Evidence considered

• PMID:19723643 documents that MET activating germline mutations cause hereditary papillary renal carcinoma via missense changes concentrated in the kinase domain, establishing missense as a disease mechanism for that phenotype, but also documents benign/polymorphic missense variation clustering in the semaphorin domain where this variant lies.
• ClinVar conditions associated with VCV000219769 include both dominant cancer-predisposition phenotypes (papillary renal cell carcinoma, hereditary cancer-predisposing syndrome) and 'Autosomal recessive nonsyndromic hearing loss 97', reflecting MET's dual dominant gain-of-function / recessive loss-of-function disease mechanisms, which complicates a uniform gene-level PP2 judgment.

Still missing

• No gnomAD missense constraint metric (missense Z-score / observed:expected ratio) available in the evidence bundle for MET
• MET disease mechanism is domain- and inheritance-dependent (dominant gain-of-function kinase-domain missense for HPRCC vs. recessive loss-of-function for MET-related hearing loss), complicating a single gene-level PP2 statement
• No formal statement characterizing MET's overall rate of benign missense variation

Sources

Reasoning

No patient phenotype, highly specific clinical findings, or disease-specific phenotype description linked to this exact variant was provided. Gene-level MET cancer context is insufficient to establish PP4.

Rule

Generic ACMG/AMP PP4: the patient's phenotype or family history is highly specific for a disease with a single-gene etiology; gene-level disease association alone is insufficient.

Evidence considered

• The case bundle contains no patient phenotype or clinical presentation for the exact variant.
• General MET oncogenic or cancer-pathway descriptions do not establish a highly specific phenotype for this variant.

Still missing

• Patient-level phenotype and diagnostic context are unavailable.
• A highly specific phenotype matching a MET-associated disorder is unavailable.

Reasoning

PP5 is restricted here to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification. ClinVar shows zero expert-panel submissions for this exact variant; the available submissions are ordinary laboratory assertions and are conflicting or uncertain.

Rule

Apply PP5 only when an exact-variant ClinVar expert panel classifies the variant as Pathogenic or Likely pathogenic; otherwise do not apply.

Evidence considered

• The exact ClinVar record is NM_000245.4(MET):c.1063G>A (p.Glu355Lys), variation 219769.
• ClinVar submission audit reports expert_panel_submissions = 0; available submissions are single-submitter laboratory assertions, with five Uncertain significance and three Likely benign laboratory counts overall.
• Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions do not trigger PP5 under the requested rule.

Still missing

• No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion is available.

Sources

Reasoning

BS2 cannot be established from the available population data alone. gnomAD contains heterozygous observations but provides no phenotype-confirmed healthy-adult ascertainment for this individual variant, and zero homozygotes were observed. Therefore, the dataset does not demonstrate unaffected individuals carrying the variant in a way that satisfies BS2.

Rule

Generic BS2: variant observed in healthy adults, including homozygotes for a dominant disorder or heterozygotes for a recessive disorder, when the phenotype and ascertainment are sufficiently informative; unphenotyped population-database carriers are insufficient by themselves.

Evidence considered

• gnomAD v4.1 reports 60 variant alleles and zero homozygotes; population database membership alone does not establish that the carriers were clinically unaffected adults.
• gnomAD v2.1 reports 7 variant alleles and zero homozygotes; no clinical phenotype or age-of-onset information for the carriers is available in the case bundle.

Still missing

• No phenotype-confirmed healthy adult carriers or disease-specific unaffected cohort data were provided.
• No homozygous individuals were observed in gnomAD, so there is no homozygote observation to evaluate.

Sources

Reasoning

Same evidentiary gap as PS3: no VCEP-specific BS3 rule exists for MET (generic ACMG fallback applies), and no validated functional assay demonstrating normal/wild-type-like activity for this variant was identified in any retrieved source. OncoKB reports no variant-specific reviewed functional data (Unknown Oncogenic Effect, not variant-specific), and the two 'functional'-themed literature entries (PMID 19723643, PMID 21904579) contain no assay results for this variant -- PMID 21904579 lists it only in a mutation-occurrence table and PMID 19723643 does not mention it at all.

Evidence considered

• OncoKB (oncokb source) queried for MET/E355K returned no variant-specific reviewed functional classification.
• Full-text review of PMID 21904579 and PMID 19723643 (the two literature entries tagged 'functional' theme) found no functional/biochemical assay data specific to this variant.

Still missing

• No functional assay data of any kind (pathogenic or benign-supporting) is available for this variant in the case bundle.
• Absence of assay evidence means neither PS3 nor BS3 can be assessed rather than defaulted to met/not_met.

Sources

Reasoning

No informative unaffected relatives known to carry the variant, or other valid non-segregation analysis, is documented.

Rule

Generic ACMG/AMP BS4 requires lack of segregation in affected family members or presence in informative unaffected relatives when the phenotype is expected to be penetrant; age, penetrance, and phenotype ascertainment must be considered.

Evidence considered

• The consolidated case-evidence bundle contains no non-segregation or unaffected-carrier observations for this variant.
• Population observations in gnomAD are not family-based non-segregation evidence and cannot establish BS4.

Still missing

• No pedigree or unaffected-relative phenotype data are documented.
• No genotypes for informative unaffected relatives are documented.
• No assessment of age-dependent penetrance, phenocopies, or phenotype ascertainment is available.

Reasoning

No applicable MET-specific VCEP/CSPEC framework was retrieved, so the generic ACMG/AMP framework was used. The case bundle contains no documented affected or unaffected individual carrying this variant with another pathogenic or likely pathogenic variant, and no phase or co-occurrence data. BP2 therefore cannot be assessed.

Rule

Generic ACMG/AMP BP2 requires observation of the variant in trans with a pathogenic or likely pathogenic variant for a dominant disorder, or in cis with a pathogenic variant for a recessive disorder, when the observation supports a benign interpretation.

Evidence considered

• The case bundle contains no family, phase, cis/trans, or co-occurrence evidence relevant to BP2.
• ClinVar classification submissions do not provide the individual-level co-occurrence evidence required for BP2.

Still missing

• No co-occurrence observations with a pathogenic or likely pathogenic variant are documented.
• No affected or unaffected individual-level genotype data are provided.
• No phase information establishes whether any additional variant is in cis or trans.

Reasoning

No patient-level evidence was provided showing that this exact variant occurs in a patient with a confirmed alternative molecular diagnosis that explains the phenotype. Conflicting ordinary ClinVar submissions and somatic COSMIC observations do not establish BP5.

Rule

Generic ACMG/AMP BP5: variant found in a patient with an alternative molecular basis for the disease; require documented patient-level alternative diagnosis and phenotype context.

Evidence considered

• The case bundle provides no affected-patient case report with an alternative molecular diagnosis explaining the phenotype.
• The exact variant's ordinary ClinVar laboratory submissions are not patient-level BP5 evidence.
• COSMIC is a somatic cancer database and does not document the germline alternative-diagnosis context required for BP5.

Still missing

• A confirmed alternative molecular diagnosis in an affected patient carrying the exact variant is unavailable.
• Patient-level phenotype and testing context are unavailable.

Reasoning

BP6 is restricted here to an exact-variant ClinVar expert-panel Benign or Likely benign classification. ClinVar shows zero expert-panel submissions for this exact variant; ordinary laboratory Likely benign assertions cannot trigger BP6.

Rule

Apply BP6 only when an exact-variant ClinVar expert panel classifies the variant as Benign or Likely benign; otherwise do not apply.

Evidence considered

• The exact ClinVar record is NM_000245.4(MET):c.1063G>A (p.Glu355Lys), variation 219769.
• ClinVar submission audit reports expert_panel_submissions = 0; the three Likely benign laboratory counts are ordinary single-submitter assertions.
• Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions do not trigger BP6 under the requested rule.

Still missing

• No exact-variant ClinVar expert-panel Benign or Likely benign assertion is available.

Sources