Starting

Initialising…

PTCH1

Final classification

VUS

PTCH1 c.536T>C · p.Leu179Pro

PTCH1

Gene

PTCH1

Transcript

NM_000264.5

HGVS · transcript:coding

NM_000264.5:c.536T>C

Consequence

N/A

GRCh38

chr9:95485733 A>G

GRCh37

chr9:98248015 A>G

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 supporting; combination = 1 moderate + 1 supporting, which maps to VUS. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 supporting; combination = 1 moderate + 1 supporting, which maps to VUS.

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 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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