About PTCH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTCH1 c.1085C>T, p.(Thr362Ile)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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
PM2Supporting
PM2 · supporting
NM_000264.5:c.1085C>T is absent from all population databases: gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Allele frequency is 0.0% in all populations, meeting PM2 at supporting level for a missense variant in an autosomal dominant disorder.
PP3Supporting
PP3 · supporting
REVEL predicts a damaging effect with a score of 0.809 (well above the 0.5 threshold). BayesDel score is 0.454 (borderline, just below 0.5). SpliceAI predicts no significant splice impact (max delta = 0.11). The REVEL meta-predictor, which integrates multiple individual in silico tools, strongly supports a deleterious effect, meeting PP3 at supporting level.
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: PM2 supporting, PP3 supporting; combination = 2 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.110 maximum delta
Recorded SpliceAI maximum delta score: 0.110. Refer to the recorded PP3/BP4 rationale for interpretation.
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; COSV59504254, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
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 · 21 not met · 1 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000264.5:c.1085C>T (p.Thr362Ile) is a missense variant in PTCH1, a gene in which heterozygous pathogenic variants cause Gorlin syndrome (nevoid basal cell carcinoma syndrome), an autosomal dominant tumor-predisposition disorder.
The variant is absent from all population databases queried: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency 0.0% in all populations). This absence meets PM2 at supporting level.
REVEL in silico meta-predictor scores the variant as 0.809, predicting a damaging effect on protein function. BayesDel scores 0.454 (borderline). SpliceAI predicts no significant splicing impact (max delta = 0.11). These computational predictions meet PP3 at supporting level.
The variant has been observed once in somatic cancers (COSMIC COSV59504254) but has not been reported in ClinVar as a germline variant, and no functional studies, de novo reports, segregation data, or case-control studies for this variant were identified in the literature.
No other ACMG/AMP criteria are met. PVS1 is not applicable because this is a missense variant and SpliceAI does not predict a null effect. PS1-PS5, PM1, PM5, PM6, PP1-PP2, PP4-PP5, BA1, BS1-BS4, BP1-BP7 are either not met or not applicable.
Applying the generic ACMG/AMP 2015 final combination rules (Richards et al. 2015, PMID:25741868), two supporting-level pathogenic criteria (PM2_Supporting, PP3_Supporting) are insufficient to reach Likely Pathogenic classification. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingNM_000264.5:c.1085C>T is absent from all population databases: gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Allele frequency is 0.0% in all populations, meeting PM2 at supporting level for a missense variant in an autosomal dominant disorder. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles)
- absent from gnomAD v4.1 (0 alleles)
- absent from gnomAD-Canada v1.0 (0 alleles)
Sources
PP3 SupportingREVEL predicts a damaging effect with a score of 0.809 (well above the 0.5 threshold). BayesDel score is 0.454 (borderline, just below 0.5). SpliceAI predicts no significant splice impact (max delta = 0.11). The REVEL meta-predictor, which integrates multiple individual in silico tools, strongly supports a deleterious effect, meeting PP3 at supporting level. Details ▾Hide ▴
Evidence considered
- REVEL: 0.809 (damaging)
- BayesDel: 0.454 (borderline)
- SpliceAI max delta: 0.11 (no splice impact)
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No established pathogenic variant at the same amino acid residue (Thr362) has been identified in ClinVar or the literature to support PS1. This variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no known pathogenic comparator at codon 362
Still missing
- Literature search for pathogenic variants at codon 362 could be performed
Sources
PS2 No published reports of de novo occurrence of NM_000264.5:c.1085C>T with confirmed paternity and maternity were identified in the literature or exploratory evidence search. Details ▾Hide ▴
Evidence considered
- No de novo reports found in literature search or ClinVar
Still missing
- Targeted search for de novo reports of p.Thr362Ile in Gorlin syndrome probands
PS3 No well-established functional studies demonstrating a damaging effect of p.Thr362Ile on PTCH1 protein function have been identified. OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional data curated
Still missing
- Functional characterization of p.Thr362Ile (e.g.
- hedgehog signaling reporter assay) would be informative
Sources
PS4 No controlled case-control data or proband counts are available to demonstrate that the prevalence of this variant in affected individuals is significantly increased compared to controls. The variant is absent from ClinVar with zero submitters. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar (0 submitters)
- absent from gnomAD population databases
Still missing
- Proband counts from clinical laboratories or published case series required for PS4 assessment
Sources
PM1 Residue 362 is not located in a statistically significant mutational hotspot as assessed by cancerhotspots.org (residue_significant: false). While position 362 may lie within the sterol-sensing domain of PTCH1, verified evidence of domain-level benign variation depletion or CSPEC/VCEP confirmation is not available to apply PM1. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue 362 not a statistically significant hotspot
Still missing
- VCEP-level domain annotation and benign variation tolerance data for the PTCH1 sterol-sensing domain would clarify PM1 applicability
PM5 No pathogenic or likely pathogenic missense variants at the same amino acid residue (Thr362) have been identified in ClinVar to serve as comparator variants. The automated PM5 candidate search returned zero same-residue candidates. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator variants identified in ClinVar
- PM5 candidate search returned no results
Still missing
- Broader literature search for missense variants at codon 362 could identify comparators
Sources
PM6 No reports of de novo occurrence of NM_000264.5:c.1085C>T without confirmation of paternity were identified in the literature or databases. Details ▾Hide ▴
Evidence considered
- No de novo reports found
Still missing
- De novo ascertainment in clinical cohorts could provide evidence
PP1 No published data demonstrating co-segregation of NM_000264.5:c.1085C>T with Gorlin syndrome or other PTCH1-associated phenotypes in affected families have been identified. Details ▾Hide ▴
Evidence considered
- No published co-segregation data available
Still missing
- Family studies documenting segregation of p.Thr362Ile with disease phenotypes
PP2 HCI prior probability scores are not available for PTCH1, so a low rate of benign missense variation cannot be computationally established. Without this or equivalent evidence, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
- HCI prior data not available for PTCH1 gene
Still missing
- Gene-level missense constraint metrics (e.g.
- Z-score
- missense depletion) would be needed to assess PP2
PP5 No reputable source has recently reported NM_000264.5:c.1085C>T as pathogenic. This variant is absent from ClinVar. Details ▾Hide ▴
BA1 NM_000264.5:c.1085C>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0.0% in all populations, far below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- Allele frequency 0.0% in all gnomAD populations
Sources
BS1 NM_000264.5:c.1085C>T is absent from all population databases (allele frequency 0.0%), well below the BS1 threshold of >0.3% for non-VCEP assessment. BS1 is not met. Details ▾Hide ▴
Evidence considered
- Allele frequency 0.0% in all populations
- below BS1 threshold
Sources
BS2 No observations of NM_000264.5:c.1085C>T in healthy adult individuals have been reported. The variant is absent from gnomAD, which includes ostensibly healthy population controls. Details ▾Hide ▴
Evidence considered
- Absent from population databases
- no healthy individual observations
Sources
BS3 No well-established functional studies demonstrating no damaging effect of p.Thr362Ile on PTCH1 protein function have been identified. Details ▾Hide ▴
Evidence considered
- No benign functional evidence identified
Still missing
- Functional assays would be needed to exclude a damaging effect
BS4 No reports of lack of segregation of NM_000264.5:c.1085C>T with disease in affected families have been identified. Details ▾Hide ▴
Evidence considered
- No non-segregation data available
Still missing
- Family data showing non-segregation would be needed for BS4
BP1 BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. PTCH1-associated Gorlin syndrome is caused by both truncating and missense variants; missense variants are a well-established mechanism of pathogenicity in PTCH1. Therefore BP1 is not applicable. Details ▾Hide ▴
Evidence considered
- PTCH1 missense variants are an established pathogenic mechanism in Gorlin syndrome
BP2 No observations of NM_000264.5:c.1085C>T in trans with a pathogenic PTCH1 variant or in cis with a pathogenic variant in any inheritance pattern have been reported. PTCH1-associated disease is autosomal dominant, making the trans scenario required for BP2. Details ▾Hide ▴
Evidence considered
- No trans or cis observations with pathogenic variants reported
BP4 REVEL score of 0.809 predicts a damaging effect, not a benign effect. Multiple in silico predictors do not support a benign impact, so BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL 0.809 (damaging)
- contradicts BP4 requirement that multiple predictors suggest no impact
Sources
BP5 No observation of NM_000264.5:c.1085C>T in a case with an alternate molecular basis for disease has been reported. Details ▾Hide ▴
Evidence considered
- No reported observation with alternate molecular cause
BP6 No reputable source has reported NM_000264.5:c.1085C>T as benign. The variant is absent from ClinVar. Details ▾Hide ▴
PS5 No reputable source has recently reported NM_000264.5:c.1085C>T as pathogenic where the underlying evidence is not available for independent review. ClinVar contains no entries for this variant. Details ▾Hide ▴
Not assessed · 1 · no assessment recorded
PP4 No patient phenotype or family history data were provided for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
- Patient phenotype data and relevant clinical history required
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000264.5:c.1085C>T is a missense variant (p.Thr362Ile) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. SpliceAI max delta score is 0.11, indicating no predicted splice impact. PVS1 cannot be applied to this variant class. Details ▾Hide ▴
Evidence considered
- Missense variant
- not a predicted null variant
- SpliceAI max delta = 0.11
- no splicing impact
Sources
PM3 N/APM3 applies to recessive disorders where a variant is detected in trans with a pathogenic variant. PTCH1-associated Gorlin syndrome is autosomal dominant; PM3 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants. NM_000264.5:c.1085C>T is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; NM_000264.5:c.1085C>T is a single-nucleotide substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_000264.5:c.1085C>T is a missense variant (p.Thr362Ile), not synonymous. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PTCH1
- Transcript
- NM_000264.5
- Coding (HGVS c.)
- NM_000264.5:c.1085C>T
- Protein (HGVS p.)
- NP_000255.2:p.(Thr362Ile)
- GRCh38
- chr9:95479130 G>A
- GRCh37
- chr9:98241412 G>A
- COSMIC
- COSV59504254
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PTCH1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.809
- BayesDel
- 0.454
How the predictions were used
PP3 SupportingREVEL predicts a damaging effect with a score of 0.809 (well above the 0.5 threshold). BayesDel score is 0.454 (borderline, just below 0.5). SpliceAI predicts no significant splice impact (max delta = 0.11). The REVEL meta-predictor, which integrates multiple individual in silico tools, strongly supports a deleterious effect, meeting PP3 at supporting level. Details ▾Hide ▴
Evidence considered
- REVEL: 0.809 (damaging)
- BayesDel: 0.454 (borderline)
- SpliceAI max delta: 0.11 (no splice impact)
Sources
BP4 REVEL score of 0.809 predicts a damaging effect, not a benign effect. Multiple in silico predictors do not support a benign impact, so BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL 0.809 (damaging)
- contradicts BP4 requirement that multiple predictors suggest no impact
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_000264.5:c.1085C>T is a missense variant (p.Thr362Ile), not synonymous. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11). REVEL score = 0.809. BayesDel score = 0.454212.
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 0.110
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000264.5%3Ac.1085C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-98241412-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-95479130-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-95479130-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000264.5%3Ac.1085…
- OncoKB ↗www.oncokb.org/gene/PTCH1/T362I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=127945998
- Cancer hotspots ↗www.cancerhotspots.org/
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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11). REVEL score = 0.809. BayesDel score = 0.454212.
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; COSV59504254, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.