Variant classification summary

NM_000264.4:c.2588G>A

PTCH1 · NP_000255.2:p.(Trp863Ter) · NM_000264.4

GRCh37: chr9:98224253 C>T · GRCh38: chr9:95461971 C>T

Gene: PTCH1 Transcript: NM_000264.4

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

PTCH1

Transcript

NM_000264.4

Protein

NP_000255.2:p.(Trp863Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: the exon 16 nonsense variant truncates PTCH1 at residue 863 of 1,448 and is expected to undergo nonsense-mediated decay.

2

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1, supporting rarity in reference populations.

Final determination: Under the generic ACMG/AMP fallback combination used by the deterministic engine, one very strong pathogenic criterion plus one supporting pathogenic criterion yields Likely Pathogenic.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	Met at very strong: the exon 16 nonsense variant truncates PTCH1 at residue 863 of 1,448 and is expected to undergo nonsense-mediated decay.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_000264.4:c.2588G>A in PTCH1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000255.2:p.(Trp863Ter). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband-specific parental genotypes or maternity and paternity confirmation are documented for this variant.
PS3	Not assessed	Not assessed: no validated assay directly tested PTCH1 p.(Trp863Ter) with variant-specific quantitative results and appropriate controls.	PMID:24840883 PMID:41748949 PMID:22670903 PMID:24523439 PMID:8782823 generic_acmg_combination_rules
PS4	Not assessed	Not assessed: no exact-variant case-control counts or validated enrichment statistic were available for PS4.	PMID:16301862 PMID:16419085
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_000264.4:c.2588G>A in PTCH1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000255.2:p.(Trp863Ter). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, supporting rarity in reference populations.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM3	N/A	Not applicable: PTCH1-associated Gorlin syndrome is autosomal dominant, and no biallelic affected-proband observation or pathogenic variant in trans is documented.	generic_acmg_combination_rules
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000264.4:c.2588G>A in PTCH1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000255.2:p.(Trp863Ter). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_000264.4:c.2588G>A in PTCH1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000255.2:p.(Trp863Ter). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no family-history or parental-testing evidence supports presumed de novo occurrence of this variant.
PP1	Not assessed	Not assessed: no informative affected-relative genotypes or meioses are reported for segregation analysis.
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_000264.4:c.2588G>A in PTCH1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000255.2:p.(Trp863Ter). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	N/A	Not applicable: the nonsense variant produces p.(Trp863Ter), outside PP3's calibrated missense and splice-region computational scope.
PP4	Not assessed	Not assessed: no patient-level phenotype or family history was provided to establish a highly specific Gorlin syndrome presentation.	clinvar PMID:16301862 PMID:16419085
PP5	Not met	Not met: the exact variant is Pathogenic in ClinVar, but the record has zero expert-panel submissions.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, far below the generic BA1 population-frequency threshold of >5%.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: gnomAD v2.1 and v4.1 show no observed allele frequency, so the variant does not exceed a disease-specific BS1 threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2	Not assessed	Not assessed: gnomAD reports no carriers or homozygotes, so the required healthy-adult observation for BS2 is unavailable.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no validated assay showed preserved PTCH1 function for p.(Trp863Ter) using quantitative results and appropriate controls.	PMID:24840883 PMID:41748949 PMID:22670903 PMID:24523439 PMID:8782823 generic_acmg_combination_rules
BS4	Not assessed	Not assessed: no genotyped affected relatives with reliable phenotype information are available to demonstrate non-segregation.
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_000264.4:c.2588G>A in PTCH1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000255.2:p.(Trp863Ter). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no second pathogenic variant or molecular phase result establishes c.2588G>A in trans or cis with another disease-causing allele.	generic_acmg_combination_rules
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000264.4:c.2588G>A in PTCH1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000255.2:p.(Trp863Ter). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: the nonsense variant produces p.(Trp863Ter), outside BP4's calibrated missense and splice-region computational scope.
BP5	Not assessed	Not assessed: no confirmed alternative molecular diagnosis or applicable BP5-specific likelihood-ratio evidence was available.	clinvar
BP6	Not met	Not met: the exact variant has no expert-panel Benign or Likely benign ClinVar classification.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000264.4:c.2588G>A in PTCH1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000255.2:p.(Trp863Ter). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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