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PTCH1c.536T>CUncertain significance
Print report
Variant interpretation report

PTCH1 c.536T>C, p.(Leu179Pro)

NM_000264.5:c.536T>C NP_000255.2:p.(Leu179Pro) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About PTCH1

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM1Moderate
PM1 · moderate

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.

PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV59472675, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 20 not met · 2 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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).

Met · 2

PM1 ModerateThe 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. Details ▾Hide ▴
Evidence considered
  • Targeted evidence recovery identified the first extracellular loop as a critical functional domain
  • PTCH1 missense variants in this domain are recurrently pathogenic in Gorlin syndrome.
Still missing
  • Domain boundaries and benign variation tolerance within the first extracellular loop would benefit from systematic UniProt/InterPro domain annotation review.
PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • absent from gnomAD v4.1 (0 alleles)
  • absent from gnomAD-Canada (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 20 · evaluated, threshold not reached

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. Details ▾Hide ▴
Evidence considered
  • ClinVar contains no entries for any nucleotide change at this codon
  • variant is absent from ClinVar.
Still missing
  • No curated database or literature evidence of an alternate nucleotide change producing L179P with a pathogenic classification.
Sources
clinvar ↗
PS2 No de novo occurrence with confirmed paternity and maternity was identified for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar is absent for this variant
  • no de novo assertions found in accessible databases or literature.
Still missing
  • No parental testing data or literature reports of de novo status available.
Sources
clinvar ↗
PS3 No well-established functional studies demonstrating a damaging effect were identified for NM_000264.5:c.536T>C (p.Leu179Pro). Details ▾Hide ▴
Evidence considered
  • OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific functional evidence curated.
Still missing
  • No in vitro functional assay data (e.g.
  • Hedgehog pathway reporter assays) for this exact variant.
Sources
oncokb ↗
PS4 No case-control studies demonstrating statistically significant enrichment of this variant in affected individuals versus controls were identified. Details ▾Hide ▴
Evidence considered
  • Variant is absent from gnomAD population databases and ClinVar
  • precluding case-control comparison.
Still missing
  • No case series or cohort studies reporting this variant in patients with Gorlin syndrome or other PTCH1-associated phenotypes.
Sources
gnomad_v2 ↗gnomad_v4 ↗clinvar ↗
PM5 No pathogenic missense variant has been established at the same amino acid residue (Leu179) via a different nucleotide change. Details ▾Hide ▴
Evidence considered
  • Automated PM5 candidate harvesting found zero same-residue comparator variants with pathogenic or likely pathogenic classifications.
Still missing
  • No ClinVar or literature evidence of another missense change at codon 179 classified as pathogenic.
Sources
pm5_candidates
PM6 No assumed de novo observation (without confirmation of paternity and maternity) was identified for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar is absent for this variant
  • no de novo claims without parental confirmation found.
Still missing
  • No literature or database entries suggesting de novo occurrence.
Sources
clinvar ↗
PP1 No cosegregation data in multiple affected family members is available for this variant. Details ▾Hide ▴
Evidence considered
  • No published pedigrees or family studies reporting segregation of c.536T>C with Gorlin syndrome or other PTCH1-associated phenotypes.
Still missing
  • No family-based cosegregation studies involving this variant.
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. Insufficient computational support for PP3. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.02 (no splice impact)
  • BayesDel 0.448 (intermediate
  • not clearly damaging)
  • REVEL score not available.
Still missing
  • REVEL score unavailable for this variant
  • additional in silico predictors would strengthen the computational assessment.
Sources
spliceai ↗bayesdel
PP5 No reputable source has reported this variant as pathogenic with unavailable evidence. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar.
Sources
clinvar ↗
BA1 The variant is absent from gnomAD v2.1 and v4.1; the allele frequency does not exceed the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0% in gnomAD v2.1 and v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from gnomAD v2.1 and v4.1; the allele frequency does not exceed the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0% in gnomAD v2.1 and v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 This variant has not been observed in healthy adults at an age where Gorlin syndrome would be fully penetrant. Details ▾Hide ▴
Evidence considered
  • Variant is absent from population databases
  • no observation in healthy adult controls.
Still missing
  • No data on presence in unaffected older adults.
BS3 No well-established functional studies demonstrating a neutral or benign effect were identified for NM_000264.5:c.536T>C. Details ▾Hide ▴
Evidence considered
  • No benign functional evidence curated in OncoKB or identified in targeted literature search.
Still missing
  • No functional assay data demonstrating no damaging effect on Hedgehog pathway signaling.
Sources
oncokb ↗
BS4 No documented lack of segregation in affected family members was identified; no unaffected carriers have been reported. Details ▾Hide ▴
Evidence considered
  • No family studies reporting non-segregation or unaffected carriers available.
Still missing
  • No segregation data in families with Gorlin syndrome or other PTCH1-associated phenotypes.
BP1 Missense variants in PTCH1, particularly those in the extracellular loops, are a well-established pathogenic mechanism for Gorlin syndrome. PTCH1 is not a gene where primarily truncating variants cause disease; missense variants are a common disease mechanism. Details ▾Hide ▴
Evidence considered
  • PTCH1 loss of function is a known disease mechanism
  • missense variants in extracellular domains are recurrently pathogenic in Gorlin syndrome (PMID:40881054
  • PMID:41816662).
Sources
pvs1_gene_context4088105441816662
BP2 No observation of this variant in trans with a known pathogenic PTCH1 variant in a healthy individual was identified. Details ▾Hide ▴
Evidence considered
  • No reports of compound heterozygosity or biallelic PTCH1 variants in unaffected individuals.
Still missing
  • No data on trans configuration with pathogenic PTCH1 variants.
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. Insufficient support for BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.02 (no splicing impact)
  • BayesDel 0.448 (intermediate).
Still missing
  • REVEL score unavailable
  • additional benign computational predictors would strengthen the assessment.
Sources
spliceai ↗bayesdel
BP5 No observation of this variant in a case with an alternate molecular basis for disease was identified. Details ▾Hide ▴
Evidence considered
  • No reports of c.536T>C co-occurring with another definitive genetic cause for the phenotype.
BP6 No reputable source has reported this variant as benign with unavailable evidence. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar.
Sources
clinvar ↗
PS5 No reputable source has recently reported this variant as pathogenic with unavailable evidence. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no reputable source classification exists.
Sources
clinvar ↗

Not assessed · 2 · no assessment recorded

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. Details ▾Hide ▴
Still missing
  • gnomAD gene-level missense constraint metrics (Z-score
  • o/e) not available in retrieved evidence. Human review of PTCH1 constraint data recommended.
PP4 No patient-specific phenotype or family history data were provided with this case; phenotypic specificity for Gorlin syndrome cannot be evaluated. Details ▾Hide ▴
Still missing
  • Patient phenotype
  • family history
  • and clinical features not available for review.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000264.5:c.536T>C is a missense variant (p.Leu179Pro) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴
Evidence considered
  • Missense variant outside PVS1 null-variant scope per ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APTCH1-associated Gorlin syndrome is autosomal dominant with haploinsufficiency as the disease mechanism; biallelic observations are not the standard disease mechanism for PM3 assessment. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AVariant is a single nucleotide substitution (c.536T>C), not a protein length-altering change (in-frame deletion/insertion, stop-loss, or initiation codon variant). Details ▾Hide ▴

No further detail was recorded.

BP3 N/AVariant is a missense substitution, not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_000264.5:c.536T>C is a missense variant (p.Leu179Pro), not a synonymous variant with no predicted splice impact. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
PTCH1
Transcript
NM_000264.5
Coding (HGVS c.)
NM_000264.5:c.536T>C
Protein (HGVS p.)
NP_000255.2:p.(Leu179Pro)
GRCh38
chr9:95485733 A>G
GRCh37
chr9:98248015 A>G
COSMIC
COSV59472675

Gene diagram

Every interpreted variant in PTCH1, mapped onto the exon structure of NM_000264.5. Select a row to find it on the plot.

PTCH1NM_000264.5
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +100 bp
0.000
SpliceAI acceptor gainat +55 bp
0.020
SpliceAI donor lossat +337 bp
0.000
SpliceAI donor gainat -85 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
0.448

How the predictions were used

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. Insufficient computational support for PP3. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.02 (no splice impact)
  • BayesDel 0.448 (intermediate
  • not clearly damaging)
  • REVEL score not available.
Still missing
  • REVEL score unavailable for this variant
  • additional in silico predictors would strengthen the computational assessment.
Sources
spliceai ↗bayesdel
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. Insufficient support for BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.02 (no splicing impact)
  • BayesDel 0.448 (intermediate).
Still missing
  • REVEL score unavailable
  • additional benign computational predictors would strengthen the assessment.
Sources
spliceai ↗bayesdel
BP7 N/ANM_000264.5:c.536T>C is a missense variant (p.Leu179Pro), not a synonymous variant with no predicted splice impact. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

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

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

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

Functional

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.

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.