MET c.737C>T, p.(Pro246Leu)

Reasoning

PM2 (Richards et al. 2015, PMID 25741868: absent in population databases, or at extremely low frequency): the variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0 and present at only 2/1,614,080 alleles (AF 1.2391e-06; 0.00012%) with 0 homozygotes in gnomAD v4.1; grpmax FAF 2.8e-07. This is an extremely low, effectively absent frequency with no homozygous observations, consistent with a rare germline disease allele. PM2 is met at supporting strength.

Rule

Generic ACMG/AMP 2015 fallback (generic_acmg_combination_rules; Richards et al. 2015, PMID 25741868): PM2 applies when the variant is absent in population databases (or at extremely low frequency if recessive).

Evidence considered

• gnomAD v4.1 (gnomad_v4): total AF 1.239095955590801e-06 (2/1,614,080 alleles), 0 homozygotes, exome AF 1.3681743491936664e-06, joint grpmax FAF 2.8e-07 - extremely low frequency consistent with PM2 (Richards et al. 2015, PMID 25741868)
• gnomAD v2.1 (gnomad_v2): variant absent
• gnomAD-Canada v1.0 (gnomad_canada): variant absent

Sources

Reasoning

Computational evidence suggests no impact on gene or gene product. Missense-path: REVEL score 0.287 falls within the ClinGen SVI-calibrated BP4-supporting range (0.183-0.290; Pejaver et al. 2022, PMID 36413997), predicting a benign/tolerated effect at supporting strength. Splice path: SpliceAI max delta 0.00 predicts no splice impact (below the 0.2 splice-altering threshold; Jaganathan et al. 2019, PMID 30661751), which corroborates but is not summed for strength (single-mechanism evaluation; BP4 strength derives from the calibrated REVEL call). BayesDel score -0.254558 was examined but is not usable (no verified published calibration threshold). BP4 is met at supporting strength.

Rule

Generic ACMG/AMP 2015 BP4 (Richards et al., PMID 25741868) with ClinGen SVI in-silico calibration (Pejaver et al. 2022, PMID 36413997): REVEL in 0.183-0.290 -> BP4 supporting; SpliceAI max delta < 0.1 -> no predicted splice impact (corroborating).

Evidence considered

• REVEL score 0.287 for 7-116699821-C-T (local REVEL v1.3 lookup) - within the ClinGen SVI BP4-supporting range 0.183-0.290 per Pejaver et al. 2022 (PMID 36413997); supports BP4 at supporting strength.
• SpliceAI max delta 0.00 for NM_001127500.2:c.737C>T (SpliceAI Lookup) - below the recommended 0.2 splice-altering threshold per Jaganathan et al. 2019 (PMID 30661751); no predicted splice impact, corroborating BP4 (not summed for strength).
• BayesDel score -0.254558 (local BayesDel noAF lookup) - not usable: no verified published calibration threshold can be cited for this predictor; treated as not available for BP4.

Still missing

• BP4 rests on a single calibrated in-silico line (REVEL 0.287, supporting) with SpliceAI corroboration; the REVEL score sits close to the upper bound of the BP4-supporting interval (0.290), so a small score revision could shift the call to the gray zone.
• BayesDel cannot provide a second calibrated missense line (no verified published threshold), and no functional/RNA-level data (e.g., BS3-style assay) are available to reinforce the benign computational direction.

Sources

Reasoning

No previously established pathogenic variant producing the same amino acid change p.(Pro246Leu) (regardless of nucleotide change) was identified in the available evidence. ClinVar variation 1758606 (NM_000245.4(MET):c.737C>T p.Pro246Leu) contains only a single-submitter Uncertain significance entry (Ambry, SCV002672101, criteria provided, no supporting PMIDs) for this exact change; per the anti-inference rule that final classification is not used as criterion-level evidence, but its presence documents that no pathogenic same-change submission exists in ClinVar. The pm5_candidates artifact reports 0 candidates seen with automated same-residue harvesting skipped (pm5_mode unknown), and the only retrieved paper (PMID:25394175) is an ACMG/NSGC referral guideline that does not mention the variant. PS1 therefore cannot be met on available evidence.

Rule

PS1 (generic ACMG/AMP 2015, PMID 25741868): Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Generic fallback used because no CSPEC/VCEP exists for MET.

Evidence considered

• clinvar: variation 1758606, NM_000245.4(MET):c.737C>T (p.Pro246Leu) - single-submitter Uncertain significance entry (SCV002672101, Ambry, criteria provided, no validated PMIDs, usable_for_criterion_leads false); documents absence of any pathogenic same-change submission, not used as criterion evidence
• pm5_candidates: pm5_mode unknown, eligible_for_classic_pm5_search false, total_candidates_seen 0, same_residue_candidates 0 - no same-residue comparator variants collected
• PMID:25394175 (reviewed, full text): general referral-indications guideline; variant not mentioned; no support for PS1

Still missing

• No systematic ClinVar/literature search was performed for alternative nucleotide changes at c.737 producing p.Pro246Leu (harvesting skipped, pm5_mode unknown)
• No ClinGen CSPEC/VCEP specification exists for MET, so no gene-specific PS1 semantics were available; generic ACMG/AMP 2015 definition applied
• Only one paper was retrieved for this case and it does not mention the variant; a dedicated same-change literature search is outstanding

Sources

Reasoning

The hotspot prong of PM1 is negative: the Cancer Hotspots query for 'MET P246' returned no statistically significant hotspot (evidence.json CANCERHOTSPOTS, search_status no_result), the variant is absent from COSMIC (no somatic cancer report), and OncoKB classifies p.Pro246Leu as 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence (not_reviewed true, citations_pmids []). The critical-functional-domain prong could not be assessed: no MET domain annotation is present in the case bundle (no domain map, no UniProt-based SEMA/IPT annotation, no VCEP PM1 text), so no critical/well-established functional domain at or around residue 246 can be asserted from available evidence. Residue 246 lies in exon 2 within the N-terminal half of the 1390-residue preproprotein by primary-sequence inspection, but that observation is not backed by a citable source in this case and is not used as evidence. PM1 is therefore not met on the available evidence.

Rule

PM1 (generic ACMG/AMP 2015, PMID 25741868): Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. Generic fallback used because no CSPEC/VCEP exists for MET.

Evidence considered

• Cancer Hotspots query 'MET P246' returned no statistically significant hotspot (evidence.json CANCERHOTSPOTS, search_status no_result) - negative for the hotspot prong of PM1; no source_registry key exists for this query, so it is described here as case-evidence context
• COSMIC search for MET c.737C>T: not previously reported in somatic cancers (evidence.json COSMIC, found false) - no cancer-recurrence/hotspot support
• oncokb: p.Pro246Leu classified 'Unknown Oncogenic Effect', is_variant_specific false, not_reviewed true, citations_pmids [] - no variant-specific functional evidence to support a critical-domain claim
• pvs1_variant_assessment: variant is a missense substitution (consequence_class missense); no domain information provided

Still missing

• MET functional-domain map (e.g., UniProt SEMA/PSI/IPT domain boundaries, HGF-binding residues) not available in the case bundle; needs external annotation source for a complete PM1 assessment
• No ClinGen CSPEC/VCEP specification exists for MET that might define gene-specific critical domains or hotspots
• Cancer Hotspots query was for residue P246 specifically; no broader hotspot-region analysis was provided

Sources

Reasoning

No pathogenic missense variant at a different amino acid at residue 246 (e.g., p.Pro246Ala, p.Pro246Ser, p.Pro246Arg) is documented in the available evidence. The pm5_candidates artifact explicitly reports pm5_mode 'unknown' with automatic same-residue candidate harvesting skipped (eligible_for_classic_pm5_search false, total_candidates_seen 0, same_residue_candidates 0), and ClinVar variation 1758606 contains no pathogenic comparator at this residue (the only ClinVar records retrieved for MET c.737C>T, variations 1758606 and 1904702, both represent this exact variant). PM5 therefore cannot be met on the available evidence; this is an absence-of-evidence determination, not a comprehensive negative search.

Rule

PM5 (generic ACMG/AMP 2015, PMID 25741868): Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Generic fallback used because no CSPEC/VCEP exists for MET.

Evidence considered

• pm5_candidates: pm5_mode unknown, eligible_for_classic_pm5_search false, same_residue_candidates 0 - no same-residue pathogenic comparator collected; recommendation level not_applicable
• clinvar: variations 1758606 and 1904702 both correspond to this exact variant (c.737C>T, p.Pro246Leu), single-submitter VUS; no different-missense pathogenic comparator at residue 246 documented

Still missing

• Automated same-residue comparator harvesting was skipped (pm5_mode unknown); a dedicated ClinVar/literature query for other missense changes at MET codon 246 is outstanding
• No ClinGen CSPEC/VCEP specification exists for MET that might define gene-specific PM5 semantics
• No ClinVar submissions for alternate changes at residue 246 were retrieved in this case bundle

Sources

Reasoning

No calibrated computational evidence predicts a damaging effect for this missense variant (MET NM_001127500.2:c.737C>T, p.Pro246Leu). Missense-path: REVEL score 0.287 is far below the ClinGen SVI PP3-supporting threshold (>=0.644; Pejaver et al. 2022, PMID 36413997). Splice path: SpliceAI max delta = 0.00 (all four delta scores 0.0) is far below the recommended 0.2 splice-altering threshold (Jaganathan et al. 2019, PMID 30661751), so no splice impact is predicted. BayesDel score -0.254558 was examined but is treated as not available for PP3/BP4 because no verified published calibration threshold can be named for it. With all available in-silico lines pointing toward neutral/tolerated effect, PP3 is not met.

Rule

Generic ACMG/AMP 2015 PP3 (Richards et al., PMID 25741868) with ClinGen SVI in-silico calibration (Pejaver et al. 2022, PMID 36413997): PP3 met only with a calibrated damaging-missense prediction (REVEL >= 0.644 for supporting) or a calibrated splice-impact prediction (SpliceAI max delta > 0.2).

Evidence considered

• REVEL score 0.287 for 7-116699821-C-T (local REVEL v1.3 lookup) - below the ClinGen SVI PP3-supporting threshold of >=0.644 per Pejaver et al. 2022 (PMID 36413997); does not support PP3.
• SpliceAI max delta 0.00 for NM_001127500.2:c.737C>T (SpliceAI Lookup) - below the recommended 0.2 splice-altering threshold per Jaganathan et al. 2019 (PMID 30661751); no predicted splice impact; does not support PP3.
• BayesDel score -0.254558 (local BayesDel noAF lookup) - not usable: no verified published calibration threshold can be cited for this predictor; treated as not available for PP3.

Still missing

• No calibrated damaging-prediction line exists for this variant: REVEL 0.287 is below the PP3-supporting threshold (>=0.644) and SpliceAI max delta 0.00 predicts no splice impact; BayesDel is excluded (no verified published calibration available).

Sources

Reasoning

PP5 (Richards et al. 2015, PMID:25741868), as operationalized for this group, is triggered only by an exact-variant ClinVar expert-panel classification of Pathogenic/Likely pathogenic. ClinVar VCV001758606 contains a single ordinary laboratory submission (Ambry Genetics, clinical testing) classified 'Uncertain significance' with review status 'criteria provided, single submitter' (1 star); expert_panels is empty and the submission audit reports 0 expert-panel submissions and 0 validated PMIDs. No exact-variant ClinGen/expert-panel Pathogenic or Likely pathogenic classification exists. The only ClinVar-linked publication (PMID:25394175) is an ACMG/NSGC referral guideline that never mentions this variant and is not a pathogenic assertion for it (and was rejected in the submission audit as an unvalidated PMID, reason 'no_valid_pmids'). Per the adjudication rule, ordinary laboratory submissions and aggregate ClinVar labels must never trigger PP5, so PP5 is not met.

Rule

ACMG/AMP 2015 PP5 (Richards et al., PMID:25741868), operationalized: triggered only by an exact-variant ClinVar expert-panel classification of Pathogenic/Likely pathogenic; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions never trigger PP5.

Evidence considered

• ClinVar VCV001758606: expert_panels empty; 0 expert-panel submissions; single 1-star VUS (Ambry Genetics); 0 validated PMIDs
• PMID:25394175 full text: referral-indications guideline, no variant-specific pathogenic assertion (0 hits for c.737C>T / p.Pro246Leu / P246)

Sources

Reasoning

NM_001127500.2:c.737C>T (MET p.Pro246Leu) is present in gnomAD v4.1 at total AF 1.2391e-06 (0.00012%; 2/1,614,080 alleles; 0 homozygotes), with highest subpopulation AF 1.69496e-06 (0.00017%) in European (non-Finnish) and grpmax FAF 2.8e-07; it is absent from gnomAD v2.1 and gnomAD-Canada v1.0. The observed frequency is more than four orders of magnitude below the generic ACMG/AMP BA1 threshold of >5% (Richards et al. 2015, PMID 25741868) and below any more permissive published BA1 calibration. BA1 is not met.

Rule

Generic ACMG/AMP 2015 fallback (generic_acmg_combination_rules; Richards et al. 2015, PMID 25741868): BA1 applies when allele frequency is >5% in a large population database (ExAC/1000 Genomes/gnomAD). No MET CSPEC/VCEP was retrieved (vcep_materials.json: 'no cspec url available'), so the generic rule governs.

Evidence considered

• gnomAD v4.1 (gnomad_v4): total AF 1.239095955590801e-06 (2/1,614,080 alleles), 0 homozygotes, best-subpopulation (NFE) AF 1.6949612192873027e-06 (2/1,179,968 alleles), grpmax FAF 2.8e-07 - far below the BA1 >5% threshold (Richards et al. 2015, PMID 25741868; framework per generic_acmg_combination_rules)
• gnomAD v2.1 (gnomad_v2): variant absent
• gnomAD-Canada v1.0 (gnomad_canada): variant absent

Still missing

• No MET-specific CSPEC/VCEP population threshold exists; assessed against the generic ACMG/AMP 2015 BA1 definition (PMID 25741868) as the governing fallback.

Sources

Reasoning

BS1 requires an allele frequency greater than expected for the disorder, with the expectation threshold derived from disease prevalence and penetrance. The observed gnomAD v4.1 total AF (1.2391e-06; 0.00012%) and best-population AF (NFE 1.69496e-06; 0.00017%) are orders of magnitude below any plausible expected-frequency threshold for a germline cancer-predisposition disorder, and the variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0. No frequency signal approaches a benign threshold; BS1 is not met.

Rule

Generic ACMG/AMP 2015 fallback (generic_acmg_combination_rules; Richards et al. 2015, PMID 25741868): BS1 applies when allele frequency is greater than expected for the disorder, where the expected frequency is estimated from disease prevalence and penetrance.

Evidence considered

• gnomAD v4.1 (gnomad_v4): total AF 1.239095955590801e-06 (0.00012%), best-subpopulation (NFE) AF 1.6949612192873027e-06 (0.00017%), 0 homozygotes, grpmax FAF 2.8e-07 - far below any plausible 'greater than expected for disorder' frequency (Richards et al. 2015, PMID 25741868)
• gnomAD v2.1 (gnomad_v2): variant absent
• gnomAD-Canada v1.0 (gnomad_canada): variant absent

Still missing

• A formal prevalence/penetrance-derived BS1 threshold for MET germline disease was not computed in this case (no MET germline disease prevalence data in the evidence bundle); not decision-limiting because the observed AF is orders of magnitude below any realistic threshold.

Sources

Reasoning

BS2 requires observation of the variant in a healthy adult individual in the state relevant to the disorder (heterozygous for a dominant disorder). gnomAD v4.1 reports 0 homozygotes and only 2 heterozygous carriers (1.24e-06 AF) who are not phenotypically confirmed as unaffected; gnomAD v2.1 and gnomAD-Canada v1.0 report the variant as absent. Two unconfirmed population carriers with no homozygotes do not satisfy BS2, and no phenotype-verified unaffected control cohort for MET germline disease is available.

Rule

Generic ACMG/AMP 2015 fallback (generic_acmg_combination_rules; Richards et al. 2015, PMID 25741868): BS2 applies when the variant is observed in a healthy adult individual for a recessive (homozygous), X-linked (hemizygous), or dominant (heterozygous) disorder.

Evidence considered

• gnomAD v4.1 (gnomad_v4): 0 homozygotes, 2 heterozygous carriers (total AC 2/1,614,080) without phenotype confirmation
• gnomAD v2.1 (gnomad_v2): variant absent
• gnomAD-Canada v1.0 (gnomad_canada): variant absent

Still missing

• No phenotype-verified healthy adult control cohort for MET germline disease was available; gnomAD carriers lack clinical confirmation of unaffected status.

Sources

Reasoning

BP1 applies only to genes in which primarily truncating variants are known to cause disease. This is not the case for MET: germline missense (activating) variants are an established disease mechanism, most notably hereditary papillary renal cell carcinoma, and gene-level curation indicates MET is dysregulated by germline or somatic mutations in multiple epithelial cancers. The pvs1_gene_context artifact reports a literature-only loss-of-function germline mechanism (supporting papers are largely gene-incidental, with PMID:26637977 addressing MET splice-regulatory mutations causing osteofibrous dysplasia), but loss-of-function support does not establish truncating variants as the primary or exclusive MET disease mechanism; no source in this case demonstrates that MET disease is predominantly truncating. Because the truncating-predominant precondition fails, BP1 is not met (evidence-symmetry: the LoF-mechanism evidence was weighed here and does not contradict this conclusion).

Rule

BP1 (generic ACMG/AMP 2015, PMID 25741868): Missense variant in a gene for which primarily truncating variants are known to cause disease. Generic fallback used because no CSPEC/VCEP exists for MET.

Evidence considered

• oncokb (gene-level): MET dysregulation via germline or somatic mutations observed in epithelial cancers including renal papillary carcinoma (gene_context.json OncoKB background; germline activating missense is an established MET mechanism) - BP1's truncating-only precondition fails
• pvs1_gene_context: lof_mechanism_supported true via literature-only review (PMID:42063004, PMID:42232598, PMID:42257088, PMID:26637977, PMID:40998418); none of these establishes truncating variants as the primary germline MET disease mechanism, and PMID:26637977 concerns MET splice-regulatory mutations in osteofibrous dysplasia - weighed per evidence symmetry, does not support BP1
• generic_acmg_combination_rules: encodes Richards et al. 2015 (PMID 25741868) generic ACMG/AMP definitions used for BP1 in the absence of any CSPEC/VCEP content

Still missing

• No ClinGen CSPEC/VCEP specification exists for MET that might define a truncating-variant proportion threshold for BP1
• Quantitative proportion of truncating vs missense pathogenic MET germline variants not provided in the case bundle (mechanism-level evidence is sufficient to fail BP1)

Sources

Reasoning

BP6 (Richards et al. 2015, PMID:25741868), as operationalized for this group, is triggered only by an exact-variant ClinVar expert-panel classification of Benign/Likely benign. ClinVar VCV001758606 contains a single ordinary laboratory submission (Ambry Genetics, clinical testing) classified 'Uncertain significance' (1 star); expert_panels is empty and the submission audit reports 0 expert-panel submissions. No exact-variant expert-panel Benign or Likely benign classification exists, and no benign assertion for this variant was found in any retrieved source. Per the adjudication rule, ordinary laboratory submissions and aggregate ClinVar labels must never trigger BP6, so BP6 is not met.

Rule

ACMG/AMP 2015 BP6 (Richards et al., PMID:25741868), operationalized: triggered only by an exact-variant ClinVar expert-panel classification of Benign/Likely benign; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions never trigger BP6.

Evidence considered

• ClinVar VCV001758606: expert_panels empty; 0 expert-panel submissions; single 1-star VUS (Ambry Genetics)
• No benign/likely benign assertion for MET c.737C>T in any retrieved source

Sources

Reasoning

PS2 requires a documented de novo occurrence of NM_001127500.2:c.737C>T (p.Pro246Leu) with confirmed maternity and paternity. No proband-level parental testing result for this variant exists in the case evidence: the sole ClinVar submission (VCV001758606, Ambry Genetics, germline, evaluated 2021-03-12) reports Uncertain significance with no de novo or parental-testing assertion and no criterion leads, and the only retrieved publication (PMID:25394175) is an ACMG/NSGC referral-indications guideline that does not mention the variant or any family data. PS2 can neither be met nor refuted with the available data and remains not assessed pending a confirmed de novo report.

Rule

ACMG/AMP 2015 PS2 (Richards et al., PMID:25741868): de novo variant with confirmed maternity and paternity; requires a specific documented parental-testing report for this variant

Evidence considered

• ClinVar VCV001758606 (SCV002672101, Ambry Genetics, germline, single submitter, 1-star) classified c.737C>T as Uncertain significance; the submission contains no de novo or parental-testing assertion (criterion leads: none)
• PMID:25394175 full text reviewed: no mention of MET, c.737C>T, p.Pro246Leu, or any de novo/segregation family data
• Generic ACMG/AMP 2015 framework applies (no MET CSPEC/VCEP retrieved; final_classification_framework found=false)

Still missing

• No parental testing (maternity/paternity confirmation) result exists for any proband carrying c.737C>T
• No documented de novo occurrence of c.737C>T with confirmed parentage identified in ClinVar or the retrieved literature

Sources

Reasoning

No well-established functional studies demonstrating a damaging effect on MET function were identified for c.737C>T (p.Pro246Leu). No ClinGen CSPEC/VCEP specification exists for MET, so the generic ACMG/AMP PS3 definition applies ('well-established functional studies show a damaging effect on the gene or gene product', Richards et al. 2015). OncoKB reports no variant-specific reviewed functional evidence for this variant (classification 'Unknown Oncogenic Effect', not_reviewed=true, is_variant_specific=false); the only ClinVar submission (single clinical laboratory, Uncertain significance) contains no functional assay data; the only retrieved publication (PMID:25394175) is a referral-indications practice guideline whose full text does not mention this variant. Available in silico data (SpliceAI max delta 0.00; REVEL 0.287) do not constitute well-established functional studies and cannot satisfy PS3. PS3 is therefore not assessed due to the absence of functional evidence; the criterion cannot be applied in either direction from current data.

Rule

PS3: Well-established functional studies show a damaging effect on the gene or gene product (generic ACMG/AMP 2015, Richards et al. PMID:25741868, per source_registry key generic_acmg_combination_rules; no MET-specific VCEP rule available)

Evidence considered

• OncoKB MET P246L entry: 'OncoKB did not identify variant-specific reviewed functional evidence for this variant'; classification 'Unknown Oncogenic Effect' with not_reviewed=true and is_variant_specific=false.
• ClinVar VCV001758606 (SCV002672101, Ambry Genetics, germline, single submitter): Uncertain significance; no functional study evidence provided; only an in silico 'tolerated' note, which is not functional evidence.
• PMID:25394175 (Hampel et al., ACMG/NSGC referral indications guideline): full text reviewed; variant c.737C>T/p.Pro246Leu is not mentioned and no functional assay data for this variant are reported.

Still missing

• No variant-specific functional assay data (e.g., cell-based MET phosphorylation/signaling assays, kinase activity assays, or validated receptor-function readouts) are available for c.737C>T/p.Pro246Leu.

Sources

Reasoning

PS4 (Richards et al. 2015, PMID:25741868) requires the prevalence of the variant in affected individuals to be significantly increased compared with controls, i.e., case-control or cohort enrichment data for the exact variant. No case-control or cohort study of MET c.737C>T (p.Pro246Leu) is available. The ClinVar record (VCV001758606) contains a single non-expert submission (Ambry Genetics, clinical testing) classified 'Uncertain significance' with review status 'criteria provided, single submitter' (1 star); the submission audit reports 0 expert-panel submissions, 0 validated PMIDs, and 0 criterion leads, so it supplies no affected-case counts. The only retrieved publication (PMID:25394175) is an ACMG/NSGC referral-indications practice guideline; a full-text search for c.737C>T, p.Pro246Leu, and residue P246 returned zero hits, so it cannot supply case or control counts for this variant. gnomAD v4.1 population frequency (AF 1.24e-06, 2/1,614,080 alleles, 0 homozygotes) is context only and is not case-control data. Evidence is insufficient; PS4 cannot be evaluated for this variant.

Rule

ACMG/AMP 2015 PS4 (Richards et al., PMID:25741868): prevalence of the variant in affected individuals significantly increased compared with controls; requires case-control or cohort enrichment data for the exact variant.

Evidence considered

• ClinVar VCV001758606 submission audit: 1 non-expert submission (Ambry Genetics), classification VUS, 1 star, 0 expert-panel submissions, 0 validated PMIDs, 0 criterion leads
• gnomAD v4.1 population frequency AF 1.24e-06 (2/1,614,080 alleles, 0 homozygotes) - context only, not case-control data
• PMID:25394175 full text: no occurrence of c.737C>T, p.Pro246Leu, or P246 (full-text search returned 0 hits)

Still missing

• No case-control or cohort enrichment study for the exact variant MET c.737C>T (p.Pro246Leu) exists; affected-case versus control counts are required to evaluate PS4.

Sources

Reasoning

PM6 requires an assumed de novo occurrence of the variant without confirmation of parentage, and is applied only when a specific de novo report for this variant is documented. No de novo report (confirmed or unconfirmed) for NM_001127500.2:c.737C>T was identified in the ClinVar submission or in the retrieved literature, so PM6 cannot be applied and remains not assessed pending such a report.

Rule

ACMG/AMP 2015 PM6 (Richards et al., PMID:25741868): assumed de novo variant without confirmation of parentage; requires a specific de novo report for this variant

Evidence considered

• ClinVar VCV001758606 submission (Ambry Genetics) contains no de novo assertion for c.737C>T; origin is listed as germline but no parental testing or de novo data are provided
• PMID:25394175 full text reviewed: guideline on referral indications only; no variant-specific or de novo case data
• Generic ACMG/AMP 2015 framework applies (no MET CSPEC/VCEP retrieved)

Still missing

• No de novo occurrence report (with or without parentage confirmation) exists for c.737C>T in ClinVar or the literature
• No proband phenotype description linked to this variant is available to contextualize a putative de novo event

Sources

Reasoning

PP1 requires co-segregation of the variant with disease in multiple affected family members. The case contains no family study for MET c.737C>T: no affected relatives were tested, no meioses were observed, and no segregation data are present in the ClinVar submission or the retrieved literature. PP1 remains not assessed pending segregation data.

Rule

ACMG/AMP 2015 PP1 (Richards et al., PMID:25741868): co-segregation of the variant with disease in multiple affected family members

Evidence considered

• ClinVar VCV001758606 submission contains no family or segregation data for c.737C>T
• Literature pass retrieved a single guideline PMID (25394175) with no segregation content; no segregation or case-series papers were identified for this variant
• Generic ACMG/AMP 2015 framework applies (no MET CSPEC/VCEP retrieved)

Still missing

• No segregation study exists for c.737C>T; no affected family members tested
• No count of informative meioses or co-segregation events available from any source

Sources

Reasoning

PP2 requires both a low rate of benign missense variation in the gene AND missense variants being a common mechanism of disease. For MET, the mechanism prong is at least partially supported: MET germline mutations are established in papillary renal cell carcinoma and other cancers (gene-level curation; OncoKB background notes MET dysregulation via germline or somatic mutations in epithelial cancers including renal papillary carcinoma), consistent with activating missense as a recognized germline disease mechanism. However, the low-benign-missense-rate prong cannot be evaluated: no gene-level missense constraint metric (e.g., gnomAD missense z-score or equivalent) is present in the case bundle, and no HCI prior is available (hci_prior found false, gene_not_supported). Because one required prong cannot be assessed, PP2 is not assessed and the specific gap is identified.

Rule

PP2 (generic ACMG/AMP 2015, PMID 25741868): Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease. Generic fallback used because no CSPEC/VCEP exists for MET.

Evidence considered

• oncokb (gene-level): MET is a receptor tyrosine kinase recurrently altered by mutation or amplification in cancer; gene_context notes dysregulation via germline or somatic mutations in epithelial cancers including renal papillary carcinoma - supports missense as a recognized (activating) mechanism prong of PP2, but no constraint metric accompanies it
• hci_prior: found false (gene_not_supported) - no gene-prior/missense-constraint surrogate available for MET
• generic_acmg_combination_rules: encodes Richards et al. 2015 (PMID 25741868) generic ACMG/AMP definitions used for PP2 in the absence of any CSPEC/VCEP content

Still missing

• Gene-level missense constraint for MET (e.g., gnomAD missense z-score or equivalent calibration of benign missense rate) not available in the case bundle
• No ClinGen CSPEC/VCEP specification exists for MET that might define gene-specific PP2 applicability
• No quantitative data on the proportion of benign vs pathogenic MET missense variants in the case bundle

Sources

Reasoning

PP4 (Richards et al. 2015, PMID:25741868) applies when the proband's phenotype or family history is highly specific for a gene with a single genetic etiology. The case bundle contains no proband clinical phenotype, family history, or clinical-summary data (case_summary.json is variant-centric and contains no index-case clinical description). The only phenotype-adjacent datum is the ClinVar condition label 'Hereditary cancer-predisposing syndrome' on the single VUS submission, which is a generic indication and does not constitute a phenotype highly specific for MET-associated disease. Without proband-level phenotype information, PP4 cannot be evaluated.

Rule

ACMG/AMP 2015 PP4 (Richards et al., PMID:25741868): phenotype or family history highly specific for a gene with a single genetic etiology.

Evidence considered

• ClinVar VCV001758606: condition label 'Hereditary cancer-predisposing syndrome' on a single non-expert VUS submission - generic indication, no proband-level detail
• Case bundle contains no clinical/phenotype summary for the index case

Still missing

• No proband phenotype or family-history data are present in the case bundle; a detailed clinical description of the index case (and evidence that the phenotype is highly specific for MET-associated disease) is required to evaluate PP4.

Sources

Reasoning

No well-established functional studies demonstrating no damaging effect were identified for c.737C>T (p.Pro246Leu). Generic ACMG/AMP BS3 requires 'well-established functional studies show no damaging effect on the gene or gene product' (Richards et al. 2015); in silico predictions alone are insufficient for BS3 under ACMG/AMP and ClinGen SVI guidance. SpliceAI max delta 0.00 and REVEL 0.287 are in silico predictions, not functional assays, and cannot support BS3. Absence from COSMIC, absence of homozygotes in gnomAD, and the single-submitter ClinVar VUS provide no functional evidence of normal MET function. BS3 is therefore not assessed due to the absence of functional evidence; the criterion cannot be applied in either direction from current data.

Rule

BS3: Well-established functional studies show no damaging effect on the gene or gene product (generic ACMG/AMP 2015, Richards et al. PMID:25741868, per source_registry key generic_acmg_combination_rules; no MET-specific VCEP rule available)

Evidence considered

• OncoKB MET P246L entry: no variant-specific functional evidence of any kind; cannot be used as evidence of normal function.
• ClinVar VCV001758606: single-submitter Uncertain significance; no functional studies; the captured in silico 'tolerated' note is not a well-established functional study and cannot support BS3.
• PMID:25394175 (Hampel et al., ACMG/NSGC referral indications guideline): full text reviewed; variant not mentioned; no functional data relevant to BS3.

Still missing

• No validated functional assay demonstrating normal MET function for c.737C>T/p.Pro246Leu (no BS3-supporting well-established functional studies identified).

Sources

Reasoning

BS4 requires lack of segregation of the variant with disease in affected family members, e.g., the variant present in unaffected relatives or absent in affected relatives in a way inconsistent with disease. No family segregation or non-segregation data exist for NM_001127500.2:c.737C>T in any case source. The very low population allele count in gnomAD v4.1 (2/1,614,080 alleles, 0 homozygotes) is population-frequency evidence relevant to BA1/BS1 and does not constitute BS4 segregation evidence. BS4 remains not assessed pending family data.

Rule

ACMG/AMP 2015 BS4 (Richards et al., PMID:25741868): lack of segregation of the variant with disease in affected family members

Evidence considered

• No family segregation or non-segregation data available in the ClinVar submission or literature for c.737C>T
• gnomAD v4.1 presence (AF 1.24e-06, 2 NFE alleles, 0 homozygotes; absent from gnomAD v2.1 and gnomAD-Canada) is population-frequency data, not BS4 segregation evidence
• Generic ACMG/AMP 2015 framework applies (no MET CSPEC/VCEP retrieved)

Still missing

• No unaffected or affected family members tested for c.737C>T; no non-segregation events documented
• No segregation analysis of any kind exists to establish or refute segregation

Sources

Reasoning

Generic ACMG/AMP 2015 (PMID 25741868, via generic_acmg_combination_rules) defines BP2 as 'Observed in trans with a pathogenic variant for a fully dominant disease/disorder; OR observed in cis with a pathogenic variant in any inheritance pattern.' No evidence in the case bundle addresses either arm: the sole ClinVar submission (VCV001758606, Ambry, VUS) reports no phase, segregation, or co-occurrence information; no proband/family data, parental testing, or literature reports involving c.737C>T are present; gnomAD allele counts (2 alleles, 0 homozygotes) cannot establish cis/trans phase. The criterion cannot be evaluated with the available evidence and is therefore not assessed pending phase/co-occurrence data.

Rule

BP2 (Richards et al. 2015, PMID 25741868): Observed in trans with a pathogenic variant for a fully dominant disease/disorder; OR observed in cis with a pathogenic variant in any inheritance pattern.

Evidence considered

• generic_acmg_combination_rules: generic ACMG/AMP 2015 fallback governs (source PMID 25741868); BP2 requires a trans-with-pathogenic (fully dominant) or cis-with-pathogenic observation.
• ClinVar VCV001758606 / SCV002672101: record consulted for phase/co-occurrence evidence; none reported.
• gnomAD v4.1: 2/1,614,080 alleles, 0 homozygotes; population data carry no cis/trans phase information.

Still missing

• No parental or phase testing results (cis vs trans) for c.737C>T relative to any pathogenic MET variant.
• No documented co-occurrence of c.737C>T with a pathogenic/likely pathogenic MET variant in any proband.
• No segregation/family data or variant-specific literature for c.737C>T in the case bundle.

Sources

Reasoning

BP5 (Richards et al. 2015, PMID:25741868) applies when a different molecular basis for the disease exists in the proband (an alternative genetic cause identified in another gene or mechanism). No proband-level molecular workup, alternative-variant findings, or documented alternative diagnosis are present anywhere in the case bundle (no clinical summary, no proband testing results, no other candidate variants). Evidence is insufficient to determine whether an alternative cause exists; BP5 cannot be evaluated.

Rule

ACMG/AMP 2015 BP5 (Richards et al., PMID:25741868): variant in a gene for which a different molecular basis for the disease exists in the proband.

Evidence considered

• Case bundle contains no proband-level molecular or clinical data relevant to an alternative cause

Still missing

• No proband-level data (molecular workup, other candidate variants, or a documented alternative diagnosis) are available to assess whether a different molecular basis for the disease exists.

Sources