LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-06
Case ID: NM_000264.5_c.2173C_T_20261006_141149
Framework: ACMG/AMP 2015
Variant classification summary

NM_000264.5:c.2173C>T

PTCH1  · NP_000255.2:p.(Pro725Ser)  · NM_000264.5
GRCh37: chr9:98231110 G>A  ·  GRCh38: chr9:95468828 G>A
Gene: PTCH1 Transcript: NM_000264.5
Final call
Benign
BS1 strong BS2 strong BP1 supporting BP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
PTCH1
Transcript
NM_000264.5
Protein
NP_000255.2:p.(Pro725Ser)
gnomAD AF
0.0008797156164390351 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Benign: BS1 (strong) - gnomAD v4.1 Middle Eastern frequency 1.4517% (grpmax FAF 1.2068%) exceeds the frequency expected for Gorlin syndrome.
2
Benign: BS2 (strong) - 1,413 adult heterozygous and 7 homozygous gnomAD v4.1 carriers are incompatible with a fully penetrant early-onset dominant disorder.
3
Benign: BP1 (supporting) - p.Pro725Ser is a missense change in PTCH1, where 87% of NBCCS-causing variants are truncating.
4
Benign: BP5 (supporting) - in the affected Gorlin syndrome case the phenotype was explained by a separate pathogenic PTCH1 c.2726dupA allele, not by p.Pro725Ser.
Final determination: Two strong benign criteria (BS1 strong, BS2 strong) meet the generic ACMG/AMP 2015 Benign combination rule (BA1 alone or two strong benign criteria), giving a Benign classification.
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 N/A PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000264.5:c.2173C>T in PTCH1 is a missense substitution predicted to produce NP_000255.2:p.(Pro725Ser). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1'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
PS1 Not met Not met: no previously established pathogenic p.Pro725Ser change exists, and this exact variant is Benign or Likely benign across all ClinVar submitters.
clinvar PMID:28733979 PMID:20485063
PS2 Not met Not met: no parental testing confirms a de novo origin, and the variant is present in gnomAD v2.1 at 252/282,872 alleles.
PMID:25741868 PMID:28733979 PMID:20485063 gnomad_v2 gnomad_v4
PS3 Not assessed Not assessed: no validated functional assay of PTCH1 p.(Pro725Ser) was reported; PMID:28733979 performed no assay and in silico tools predicted a neutral effect.
generic_acmg_combination_rules oncokb PMID:25741868 PMID:26467025 PMID:28492532 PMID:28733979 PMID:20485063
PS4 Not met Not met: no case-control enrichment exists, and the variant is carried in gnomAD v4.1 at AF 0.00088 with seven homozygotes.
clinvar gnomad_v2 gnomad_v4 PMID:28733979 PMID:20485063 PMID:22703879 PMID:24728327 PMID:25741868
PM1 Not met Not met: PTCH1 has no mutational hotspot and residue 725 is not a VCEP-approved critical domain, while gnomAD v4.1 carries 1,420 alleles with 7 homozygotes there.
PMID:28733979 gnomad_v4 gnomad_v2 clinvar
PM2 Not met Not met: gnomAD frequency ~0.088% (v4.1 and v2.1) is about nine-fold above the 0.0001 PM2 threshold.
gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
PM3 N/A Not applicable: PTCH1-related Gorlin syndrome is autosomal dominant, whereas PM3 applies only to recessive disorders with a pathogenic variant detected in trans.
PMID:20485063 PMID:28733979 PMID:25741868 clinvar
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_000264.5:c.2173C>T in PTCH1 is a missense substitution predicted to produce NP_000255.2:p.(Pro725Ser). 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 Not met Not met: the only other residue-725 missense variants, p.Pro725Arg and p.Pro725His, are Uncertain significance or Benign in ClinVar, not established pathogenic.
clinvar pm5_candidates PMID:28733979
PM6 Not met Not met: no source assumes a de novo origin, and p.P725S recurs in gnomAD v4.1 with 1,420 alleles including 7 homozygotes.
PMID:25741868 PMID:28733979 PMID:20485063 gnomad_v2 gnomad_v4
PP1 Not assessed Not assessed: zero informative meioses, because the only genotyped relatives in the reported cohort carried different, truncating PTCH1 variants.
PMID:25741868 PMID:28733979 PMID:20485063
PP2 Not met Not met: PTCH1 disease variants are predominantly truncating (17 of 19 novel mutations; 87% of patients), so missense change is not the primary mechanism.
PMID:28733979 pvs1_gene_context PMID:22703879
PP3 Not met Not met: REVEL 0.299 for the p.(Pro725Ser) missense variant is below the PP3 supporting threshold of 0.644 under the ClinGen SVI calibration.
revel generic_acmg_combination_rules
PP4 Not assessed Not assessed: no proband phenotype or family history is available to test specificity for a single-gene disorder.
PP5 Not met Not met: the exact variant's ClinVar record has no expert-panel submission (expert_panels empty; highest review status 2-star, benign).
clinvar PMID:15604628 PMID:25741868
BA1 Not met Not met: the highest gnomAD frequency anywhere is 1.45% (Middle Eastern), far below the 5% BA1 threshold.
gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
BS1 Met Met (strong): gnomAD v4.1 Middle Eastern frequency 1.4517% and grpmax FAF 1.2068% exceed the 1% BS1 threshold.
gnomad_v2 gnomad_v4 PMID:25741868
BS2 Met Met (strong): 1,413 adult heterozygous and 7 homozygous gnomAD v4.1 carriers are incompatible with a fully penetrant dominant disorder.
gnomad_v2 gnomad_v4 PMID:20485063
BS3 Not assessed Not assessed: no functional assay demonstrated normal PTCH1 function for p.(Pro725Ser); the only relevant study (PMID:28733979) performed no assay and reported in silico neutral predictions.
generic_acmg_combination_rules oncokb PMID:25741868 PMID:26467025 PMID:28492532 PMID:28733979 PMID:20485063
BS4 Not assessed Not assessed: no family has been genotyped for p.P725S, so lack of segregation cannot be demonstrated.
PMID:25741868 PMID:28733979 PMID:20485063 gnomad_v2 gnomad_v4
BP1 Met Met at supporting strength: PTCH1 NBCCS variants are primarily truncating, with 17 truncating versus 2 missense novel mutations and truncating changes in 87% of patients.
PMID:28733979 pvs1_gene_context PMID:22703879
BP2 Not met Not met: the only co-occurrence, p.(Pro725Ser) with pathogenic PTCH1 c.2726dupA in one Gorlin-Goltz patient, has undetermined cis/trans phase, so the required BP2 observation is absent.
PMID:20485063 PMID:28733979 PMID:25741868 clinvar
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_000264.5:c.2173C>T in PTCH1 is a missense substitution predicted to produce NP_000255.2:p.(Pro725Ser). 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 Not met Not met: REVEL 0.299 exceeds the <=0.29 BP4 supporting threshold, placing this missense variant in the gray zone where BP4 is not satisfied.
revel generic_acmg_combination_rules
BP5 Met Met (supporting): in the affected Gorlin syndrome case, disease was explained by pathogenic PTCH1 c.2726dupA, not by p.P725S (PMID:20485063).
PMID:20485063 PMID:25741868
BP6 Not met Not met: no exact-variant expert-panel benign classification exists; the ClinVar record is 2-star from ordinary laboratory submitters.
clinvar PMID:25741868
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_000264.5:c.2173C>T in PTCH1 is a missense substitution predicted to produce NP_000255.2:p.(Pro725Ser). 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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