Classification rationale

PM1PM2 VUS

PTCH1 c.536T>C

PM1 (moderate): p.Leu179Pro is located within the first extracellular loop (aa 115–210) of PTCH1, a critical Hedgehog ligand-binding domain that is a well-established mutational hotspot in Gorlin syndrome. PM2 (supporting): NM_000264.5:c.536T>C is absent from gnomAD v2.1 and v4.1 population databases (allele frequency 0%), consistent with a rare variant.¹ Overall, one moderate criterion (PM1) and one supporting criterion (PM2) are met. Per the ACMG/AMP 2015 generic combination rules (PMID:25741868), this combination is insufficient to reach Likely Pathogenic (minimum: 3 moderate, 2 moderate + 2 supporting, or 1 moderate + 4 supporting). The variant is classified as a Variant of Uncertain Significance (VUS).²

PM1 + PM2 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 generic_acmg_combination_rules

Gene diagram · NM_000264.5 · variants mapped to exon structure

PTCH1 NM_000264.5

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM1 moderate Pathogenic

The variant p.Leu179Pro is located at amino acid 179 within the first extracellular loop (approximately aa 115–210) of PTCH1, a critical Hedgehog ligand-binding domain where pathogenic missense variants cluster in Gorlin syndrome. This domain is a well-established mutational hotspot for this disorder.

Targeted evidence recovery identified the first extracellular loop as a critical functional domainPTCH1 missense variants in this domain are recurrently pathogenic in Gorlin syndrome.

✓

PM2 supporting Pathogenic

NM_000264.5:c.536T>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with an allele frequency well below the 0.1% threshold for PM2 in non-VCEP ACMG/AMP assessment.

Absent from gnomAD v2.1 (0 alleles)absent from gnomAD v4.1 (0 alleles)absent from gnomAD-Canada (0 alleles).

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied

Pathogenic

PS1 No evidence was identified of a different nucleotide change at codon 179 resulting in the same p.Leu179Pro amino acid substitution that has been classified as pathogenic.

PS2 No de novo occurrence with confirmed paternity and maternity was identified for this variant.

PS3 No well-established functional studies demonstrating a damaging effect were identified for NM_000264.5:c.536T>C (p.Leu179Pro).

PS4 No case-control studies demonstrating statistically significant enrichment of this variant in affected individuals versus controls were identified.

PM5 No pathogenic missense variant has been established at the same amino acid residue (Leu179) via a different nucleotide change.

PM6 No assumed de novo observation (without confirmation of paternity and maternity) was identified for this variant.

PP1 No cosegregation data in multiple affected family members is available for this variant.

PP2 Missense constraint metrics for PTCH1 (e.g., gnomAD missense Z-score or o/e ratio) were not retrieved; the low rate of benign missense variation required by PP2 cannot be evaluated without this data.

PP3 Multiple lines of computational evidence do not converge on a deleterious prediction: SpliceAI predicts no splicing impact (max delta score 0.02), BayesDel score is intermediate (0.448), and REVEL is unavailable.

PP4 No patient-specific phenotype or family history data were provided with this case; phenotypic specificity for Gorlin syndrome cannot be evaluated.

PP5 No reputable source has reported this variant as pathogenic with unavailable evidence.

Benign

BA1 The variant is absent from gnomAD v2.1 and v4.1; the allele frequency does not exceed the 1% BA1 threshold.

BS1 The variant is absent from gnomAD v2.1 and v4.1; the allele frequency does not exceed the 0.3% BS1 threshold.

BS2 This variant has not been observed in healthy adults at an age where Gorlin syndrome would be fully penetrant.

BS3 No well-established functional studies demonstrating a neutral or benign effect were identified for NM_000264.5:c.536T>C.

BS4 No documented lack of segregation in affected family members was identified; no unaffected carriers have been reported.

BP1 Missense variants in PTCH1, particularly those in the extracellular loops, are a well-established pathogenic mechanism for Gorlin syndrome.

BP2 No observation of this variant in trans with a known pathogenic PTCH1 variant in a healthy individual was identified.

BP4 Multiple lines of computational evidence do not converge on a benign prediction: SpliceAI shows no splicing impact (delta 0.02), but BayesDel is intermediate (0.448) and REVEL is unavailable.

BP5 No observation of this variant in a case with an alternate molecular basis for disease was identified.

BP6 No reputable source has reported this variant as benign with unavailable evidence.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

This variant is absent from gnomAD-Canada.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.447969.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTCH1, a tumor suppressor and inhibitor of the hedgehog pathway, is recurrently mutated in basal cell carcinoma.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59472675, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Re-run this variant?