TERT c.1812A>G, p.(Ala604=)

Reasoning

NM_198253.2:c.1812A>G is a synonymous variant (NP_937983.2:p.(Ala604=)) with no TERT-specific VCEP CSPEC BP7 rule retrieved for this case. Under the generic ACMG/AMP fallback, synonymous variants are evaluated via the SpliceAI-only splice-impact path: SpliceAI max delta score = 0.034, well below the 0.1 threshold, indicating no predicted splice disruption at any of the four splice-site categories (DS_AG=0.026, DS_AL=0.001, DS_DG=0.034, DS_DL=0.022). This supports the benign-direction, synonymous-variant-specific code BP7 at supporting strength.

Rule

generic_acmg_fallback: synonymous variant -> SpliceAI-only path; SpliceAI max delta < 0.1 supports BP7 (supporting) for no predicted splice impact.

Evidence considered

• SpliceAI max delta score = 0.034 (DS_AG=0.026, DS_AL=0.001, DS_DG=0.034, DS_DL=0.022) indicates no predicted splice impact, below the 0.1 threshold in the generic fallback splice-path calibration for synonymous variants.
• No TERT-specific ClinGen VCEP CSPEC was retrieved (vcep_materials.json summaries={}, final_classification_framework.json found=false), so the generic_acmg_classification_rules.md SpliceAI-based threshold governs BP7 application for this synonymous variant.

Still missing

• The bundle contains no nucleotide conservation score (e.g. phyloP/GERP) for this position; the original 2015 ACMG/AMP BP7 wording also references the variant nucleotide not being highly conserved, and that sub-criterion could not be independently verified from the available evidence bundle.

Sources

Reasoning

PM2 requires absence or near-absence from population databases. This variant is clearly present in gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, with overall allele frequencies of 0.240019%, 0.336879%, and 0.266015%, respectively. Therefore PM2 is not met.

Rule

Generic PM2: absent from or nearly absent from population databases, subject to applicable disease-specific specifications.

Evidence considered

• gnomAD v2.1: 678/282478 alleles, AF 0.00240019, with 0 homozygotes.
• gnomAD v4.1: 5436/1613634 alleles, AF 0.00336879, with 10 homozygotes.
• gnomAD-Canada v1.0: 49/18420 alleles, AF 0.00266015, with 1 homozygote.
• The variant is not absent or rare enough in the available population datasets to support PM2.

Sources

Reasoning

NM_198253.2:c.1812A>G is a synonymous change (NP_937983.2:p.(Ala604=)); no ClinGen VCEP CSPEC is available for TERT (final_classification_framework.json / vcep_materials.json both report found=false, generic_acmg_fallback used), so the lab's generic in-silico calibration applies. This variant is not a missense substitution, so the REVEL missense path does not apply (and REVEL itself was not found/scored for this variant - revel.score=null). Under the splice-impact path (used for intronic/synonymous/non-canonical-splice-position variants per generic_acmg_classification_rules.md), SpliceAI reports a maximum delta score of only 0.034 (DS_AG 0.026, DS_AL 0.001, DS_DG 0.034, DS_DL 0.022), far below the 0.2 threshold required for PP3. No pathogenic-direction computational evidence is present.

Rule

generic_acmg_fallback: non-missense (synonymous) variant -> SpliceAI-only path; SpliceAI max delta > 0.2 required for PP3 (supporting); observed 0.034 does not meet this.

Evidence considered

• SpliceAI max delta score = 0.034 (DS_AG=0.026, DS_AL=0.001, DS_DG=0.034, DS_DL=0.022), below the 0.2 pathogenic-supporting threshold used in the generic in-silico calibration for non-missense variants.
• Variant is synonymous (p.Ala604=), so the REVEL missense-path threshold in the generic calibration does not apply; REVEL score was not found for this variant (revel.found=false).
• No TERT-specific ClinGen VCEP CSPEC PP3/BP4 lookup was retrieved for this case (vcep_materials.json summaries={}, final_classification_framework.json found=false); generic_acmg_classification_rules.md fallback governs.

Sources

Reasoning

PP5 is not met. The exact variant is reported in ClinVar as Benign/Likely benign with criteria provided by single submitters and no expert-panel submission; ordinary laboratory submissions and aggregate labels are explicitly ineligible for PP5.

Evidence considered

• ClinVar variation 165379 corresponds to NM_198253.3(TERT):c.1812A>G (p.Ala604=) and reports Benign/Likely benign submissions, with review status indicating no expert-panel classification.
• The case summary records zero expert-panel submissions; therefore the exact-variant expert-panel requirement for PP5 is not satisfied.

Sources

Reasoning

The variant is far below the generic BA1 population-frequency threshold of greater than 5%. gnomAD v4.1 reports AF 0.00336879 (0.336879%), and the highest reported subpopulation AF is 0.00628293 (0.628293%) in Ashkenazi Jewish individuals; gnomAD v2.1 reports AF 0.00240019 and its highest subpopulation AF is 0.00579710. gnomAD-Canada reports AF 0.00266015. These observations do not meet BA1.

Rule

Generic BA1: allele frequency greater than 5%.

Evidence considered

• gnomAD v4.1: 5436/1613634 alleles, AF 0.00336879, with 10 homozygotes; Ashkenazi Jewish AF 0.00628293.
• gnomAD v2.1: 678/282478 alleles, AF 0.00240019, with no homozygotes; Ashkenazi Jewish AF 0.00579710.
• gnomAD-Canada v1.0: 49/18420 alleles, AF 0.00266015, with 1 homozygote.
• Generic ACMG/AMP BA1 interpretation uses an allele frequency greater than 5% as the standalone benign threshold; this case does not reach that threshold.

Sources

Reasoning

BP6 is not met. Although ClinVar contains Benign/Likely benign submissions for the exact variant, there is no exact-variant ClinVar expert-panel classification; single-submitter laboratory assertions and aggregate ClinVar labels cannot trigger BP6.

Evidence considered

• ClinVar variation 165379 reports Benign/Likely benign classifications for the exact variant, but the available record has no expert-panel submission and is composed of laboratory submissions.
• Because the required exact-variant expert-panel Benign or Likely benign classification is absent, BP6 cannot be applied.

Sources

Reasoning

No case-level evidence documents a confirmed de novo occurrence of NM_198253.2:c.1812A>G in an affected proband with parental testing. The bundle contains no proband-parent genotypes, maternity/paternity confirmation, parental allele status, or mosaicism assessment sufficient to evaluate PS2.

Rule

Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history, with confirmed maternity/paternity; strength depends on the quality and completeness of de novo evidence. No gene-specific specification was retrieved.

Evidence considered

• The case summary identifies TERT NM_198253.2:c.1812A>G (p.Ala604=), but does not report a proband-parent trio or de novo finding.
• The consolidated evidence bundle contains population, ClinVar, splicing, and general literature records but no documented parental testing or de novo observation for this variant.

Still missing

• Affected proband genotype and phenotype documentation
• Validated testing results for both biological parents showing absence of the variant
• Confirmation of parentage and assessment for parental mosaicism
• Case-level publication or laboratory record describing the de novo event

Reasoning

No VCEP-specific framework exists for TERT (cspec not found; case runs under generic ACMG fallback, framework_mode=generic_acmg, precedence_rank 3/generic_acmg_fallback). No functional/well-established assay data (splicing minigene, telomerase activity assay, RT-PCR, etc.) for this specific variant was found anywhere in the prefetch, evidence, literature_pass, or vcep_materials sections of the bundle. The literature pass returned only background/general-interest and case-observation papers (PMID:24033266, PMID:25741868 methodology papers; PMID:20301408, PMID:20301779, PMID:26389258, PMID:26389333 GeneReviews/PDQ overview chapters) with no PS3/BS3 candidate_criteria flags and no variant-specific functional data. In silico SpliceAI prediction shows negligible splice impact (max delta score 0.034), which is not a validated functional assay and cannot support PS3.

Evidence considered

• Variant is synonymous (NP_937983.2:p.(Ala604=)); no functional wet-lab or splicing assay data for this variant was located in prefetch.json, evidence.json, literature_pass.json, or vcep_materials.json.
• SpliceAI predicts no significant splice impact for this variant (max delta score = 0.034; DS_AG=0.026, DS_AL=0.001, DS_DG=0.034, DS_DL=0.022), which is an in silico prediction, not a validated functional assay, and therefore cannot be used to satisfy PS3.
• case_summary.json cspec.found = false and vcep_materials.json final_classification_framework.found = false with source = generic_acmg_fallback, confirming no TERT-specific VCEP functional-evidence specification is available for this case.

Still missing

• No published or unpublished functional assay (e.g., telomerase activity, TRAP assay, minigene splicing assay) evaluating this specific variant (NM_198253.2:c.1812A>G, p.Ala604=) was identified.
• No TERT-specific VCEP functional-assay specification was available to define validated assay types or PS3 strength calibration for this gene.

Reasoning

No case-control enrichment dataset, affected-case count with an appropriate comparator, or statistically interpretable prevalence evidence for the exact NM_198253.2:c.1812A>G variant was available in the reviewed case bundle.

Evidence considered

• The case bundle contains no exact-variant case-control table, odds ratio, p-value, or validated phenotype prevalence comparison for NM_198253.2:c.1812A>G.
• ClinVar lists this exact variant, but its available record is an aggregate of laboratory submissions and does not provide usable PS4 case-control evidence.

Still missing

• Exact-variant affected-case and control counts or a validated case-control enrichment analysis are unavailable.
• The literature candidates were ClinVar citation trails without accessible variant-specific full text in this case, so PS4 cannot be inferred from their classifications or titles.

Reasoning

No applicable TERT-specific VCEP/CSPEC framework was retrieved, so the generic ACMG/AMP framework applies. The case bundle provides no affected-proband observations, second pathogenic/likely pathogenic allele, phase information, or inheritance data for this variant. PM3 therefore cannot be assessed.

Rule

Generic ACMG/AMP PM3: pathogenic or likely pathogenic evidence for a recessive disorder when the evaluated variant is observed in trans with a pathogenic variant; phase and affected-proband context must be established before application.

Evidence considered

• The consolidated case-evidence bundle states that no gene-specific TERT VCEP/CSPEC framework was found and that generic ACMG/AMP 2015 is the fallback framework.
• The consolidated case-evidence bundle contains no documented affected proband, compound-heterozygous observation, pathogenic allele in trans, or phase/inheritance observation for NM_198253.2:c.1812A>G.

Still missing

• Affected-proband genotype and phenotype data are not available.
• No pathogenic or likely pathogenic variant in trans is documented.
• No phase determination (trans or cis) is documented.
• The relevant inheritance model for the evaluated condition is not specified in the case evidence.

Sources

Reasoning

No case-level evidence supports an assumed de novo occurrence of NM_198253.2:c.1812A>G without documented parental testing. The available records do not identify an affected proband, a family history assessment, or parental genotypes that would permit PM6.

Rule

Generic ACMG/AMP PM6: assumed de novo occurrence in a patient with the disease and no family history, without confirmation of maternity/paternity. No gene-specific specification was retrieved.

Evidence considered

• No de novo or assumed-de-novo case description is present in the consolidated case-evidence bundle.
• ClinVar classifications and population observations do not establish de novo status and were not used as evidence for PM6.

Still missing

• A documented affected proband and relevant phenotype
• Evidence that the variant was observed as apparently de novo
• Parental testing or, if unavailable, a clearly documented basis for assuming de novo status
• Family history and parentage information

Reasoning

No informative familial segregation data are provided for NM_198253.2:c.1812A>G. The bundle does not report affected or unaffected relatives, variant-positive or variant-negative relatives, phase, number of informative meioses, or a pedigree from which segregation strength could be calculated.

Rule

Generic ACMG/AMP PP1: cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease; strength may be increased with multiple informative meioses under an applicable calibrated framework. No gene-specific specification was retrieved.

Evidence considered

• The consolidated case-evidence bundle contains no family pedigree, relative genotypes, segregation counts, or informative meioses for this variant.
• Variant-level ClinVar and population records do not provide familial segregation evidence and were not used to infer PP1.

Still missing

• Pedigree with phenotype status for relatives
• Genotypes of affected and unaffected relatives
• Number of informative meioses and segregation pattern
• Phenotype consistency and assessment of reduced penetrance or age-dependent disease

Reasoning

No patient-level phenotype or highly specific phenotype pattern linked to this exact variant was provided; gene-level disease descriptions and ClinVar condition labels are insufficient to establish PP4.

Evidence considered

• The case bundle does not provide a clinical phenotype for the individual carrying NM_198253.2:c.1812A>G.
• ClinVar condition labels are not patient-level phenotype evidence and were not used to infer PP4.

Still missing

• A documented patient phenotype and assessment of its specificity for a TERT-related disorder are unavailable.

Reasoning

The variant is common in multiple population datasets (gnomAD v4.1 overall AF 0.336879%, maximum reported subpopulation AF 0.628293%; 10 observed homozygotes), which could be inconsistent with a highly penetrant rare TERT-related disorder. However, the case bundle provides no disorder-specific prevalence, penetrance, age-of-onset, or maximum credible allele-frequency threshold for the relevant TERT condition(s). Because the observed frequency cannot be compared to a documented disease-specific expectation without those inputs, BS1 is not assessed rather than applied from a generic frequency impression.

Rule

Generic BS1: allele frequency greater than expected for the disorder; application requires a disease-specific expected-frequency threshold.

Evidence considered

• gnomAD v4.1 reports AF 0.00336879, 10 homozygotes, and maximum reported subpopulation AF 0.00628293 in Ashkenazi Jewish individuals; non-Finnish European AF is 0.00393212 with 7 homozygotes.
• gnomAD v2.1 reports AF 0.00240019 and no homozygotes; gnomAD-Canada reports AF 0.00266015 and 1 homozygote.
• Generic ACMG/AMP BS1 requires an allele frequency greater than expected for the disorder, but the case bundle contains no disorder-specific prevalence, penetrance, or maximum credible allele-frequency threshold.
• Population datasets do not establish that the observed homozygotes are phenotypically unaffected, and the available data do not resolve age-dependent or reduced penetrance.

Still missing

• A documented prevalence and penetrance model for the relevant TERT-related disorder is needed to calculate or justify a maximum credible allele frequency.
• The clinical significance and age-dependent penetrance of this synonymous TERT variant are not established by the population data alone.

Sources

Reasoning

gnomAD v4.1 reports 10 homozygotes, and gnomAD-Canada reports 1 homozygote, but the case bundle does not provide phenotype, age, ascertainment, or clinical follow-up for those individuals. Presence of homozygotes in a reference population is not sufficient by itself to establish that they are healthy adults unaffected by a relevant TERT-related disorder, particularly for conditions with possible late onset or reduced penetrance. BS2 is therefore not assessed.

Rule

Generic BS2: observation in healthy adult individuals, including homozygotes when relevant to the inheritance model; population homozygote counts without phenotype data are insufficient.

Evidence considered

• gnomAD v4.1 reports 10 total homozygotes, including 7 in the non-Finnish European population and 1 in the South Asian population.
• gnomAD-Canada reports 1 homozygote.
• The population records provide allele counts and homozygote counts but do not provide individual-level phenotype, age, or clinical follow-up sufficient to establish unaffected healthy adults.

Still missing

• Phenotypic and age-at-assessment information for the observed homozygotes is unavailable.
• The relevant inheritance model, disease penetrance, and expected clinical impact of homozygosity for this synonymous TERT variant are not documented in the case bundle.

Sources

Reasoning

No VCEP-specific framework exists for TERT (cspec not found; generic ACMG fallback in effect). No functional assay data demonstrating normal/wild-type activity for this specific variant was found in any bundle section. In silico SpliceAI shows negligible splice disruption (max delta 0.034), consistent with no predicted splicing effect, but this is not a validated functional assay under BS3 and cannot on its own establish BS3.

Evidence considered

• No wet-lab functional assay data for this variant was located in prefetch.json, evidence.json, literature_pass.json, or vcep_materials.json.
• SpliceAI predicts no significant splice impact for this variant (max delta score = 0.034), an in silico prediction insufficient on its own to satisfy BS3, which requires a validated functional study.

Still missing

• No published or unpublished functional assay (telomerase activity, splicing assay, minigene, etc.) with a normal/wild-type-like result for this specific variant was identified.
• No TERT-specific VCEP functional-assay specification was available to define validated assay types or BS3 strength calibration for this gene.

Reasoning

No valid non-segregation evidence is available. The case bundle does not document unaffected relatives who were tested and found to carry NM_198253.2:c.1812A>G, nor does it provide phenotype evaluations, ages, penetrance context, or informative meioses needed to assess BS4.

Rule

Generic ACMG/AMP BS4: lack of segregation in affected family members, or presence of the variant in unaffected family members, when the family structure and phenotype assessment make non-segregation informative. No gene-specific specification was retrieved.

Evidence considered

• No affected/unaffected relative comparison or non-segregation observation is reported in the consolidated case-evidence bundle.
• Population frequency, ClinVar classification, and general disease descriptions do not constitute BS4 evidence and were not used for this criterion.

Still missing

• Tested unaffected relatives with reliable genotype results
• Adequate age and clinical evaluation to establish unaffected status
• Family structure and informative meioses
• Penetrance and phenotype-consistency assessment for TERT-related disease

Reasoning

No applicable TERT-specific VCEP/CSPEC framework was retrieved, so the generic ACMG/AMP framework applies. The case bundle provides no observation of this variant in cis with a pathogenic variant or in trans with a pathogenic variant in a disorder where such an allelic observation supports benignity. BP2 therefore cannot be assessed.

Rule

Generic ACMG/AMP BP2: the variant is observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant for any disorder; phasing and the applicable inheritance model must be established before application.

Evidence considered

• The consolidated case-evidence bundle states that no gene-specific TERT VCEP/CSPEC framework was found and that generic ACMG/AMP 2015 is the fallback framework.
• The consolidated case-evidence bundle contains no documented cis/trans phase observation, paired pathogenic variant, or individual-level allelic context for NM_198253.2:c.1812A>G.

Still missing

• No phasing data are available to determine cis or trans configuration.
• No paired pathogenic variant is documented in the relevant individual(s).
• No affected/unaffected individual-level genotype context is available.
• The relevant inheritance model for the evaluated condition is not specified in the case evidence.

Sources

Reasoning

No evidence was supplied that the patient's phenotype is explained by an alternative molecular etiology, and no patient-level diagnostic context was available to evaluate BP5.

Evidence considered

• The reviewed bundle contains no patient-level alternative molecular diagnosis or test result that could support BP5.

Still missing

• Patient-level phenotype, diagnostic testing, and evidence for an alternative molecular cause are unavailable.