About PTCH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTCH1 c.1913G>A, p.(Arg638His)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
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: 1
Benign evidence criteria: 3
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present in gnomAD at very low frequency overall (v2.1: 33/282,644 alleles, AF=0.012%; v4.1: 126/1,613,872 alleles, AF=0.008%), below the 0.1% threshold for PM2. No homozygotes are observed. The African/African American subpopulation AF is 0.112% in v2.1 (borderline above 0.1%) but 0.087% in v4.1, supporting overall rarity.
Benign criteria applied · 3
BS2Supporting
BS2 · supporting
This variant has been observed in multiple individuals within gnomAD population databases (33 alleles in v2.1, 126 alleles in v4.1) who are presumed healthy adults based on gnomAD's exclusion of severe pediatric disease. Gorlin syndrome is a highly penetrant autosomal dominant disorder with early onset; observation of this variant in population controls at this frequency is consistent with a benign or low-penetrance variant.
BP4Supporting
BP4 · supporting
Multiple in silico predictors support a benign effect for this variant: REVEL score 0.378 (below the 0.5 pathogenic threshold), BayesDel score -0.243824 (predicting benign), and SpliceAI max delta 0.05 (no predicted splicing impact). These represent multiple independent lines of computational evidence suggesting no functional consequence.
BP6Supporting
BP6 · supporting
Five clinical diagnostic laboratories classify this variant as Likely benign (4 labs: GeneDx, Ambry Genetics, Eurofins Ntd, Sema4) or Benign (1 lab: Labcorp Genetics/Invitae) in ClinVar (ClinVar ID 220182). One additional laboratory (ARUP) classifies as VUS. While the review status is 'criteria provided, single submitter' (1-star, below the 3-star expert panel threshold), the consensus across multiple independent clinical laboratories reporting with criteria supports BP6 at supporting benign level.
Recorded classification: Likely benign
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, BS2 supporting benign, BP4 supporting benign, BP6 supporting benign; combination = 1 supporting + 3 supporting benign, which maps to Likely Benign.
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
126 / 1,613,872 alleles
gnomAD v4.1: 126 / 1,613,872 alleles. Recorded AF 7.80731e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000116755; MAF= 0.01168%, 33/282644 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00112215; MAF= 0.11222%, 28/24952 alleles, homozygotes = 0); grpmax FAF= 0.00101842.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.050 maximum delta
Recorded SpliceAI maximum delta score: 0.050. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
6 reported laboratory submissions
4 Likely benign · 1 Benign · 1 Uncertain significance. ClinVar API review status: criteria provided, conflicting classifications.
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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: 4 met · 17 not met · 2 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
This variant is a missense change (p.Arg638His) in PTCH1, a gene in which loss-of-function is an established mechanism for Gorlin syndrome (nevoid basal cell carcinoma syndrome), an autosomal dominant disorder with high penetrance and early onset.
The variant is present in gnomAD population databases at low frequency overall (v2.1: 33/282,644 alleles, AF=0.012%; v4.1: 126/1,613,872 alleles, AF=0.008%), with the highest subpopulation frequency in Africans/African Americans (0.112% in v2.1). No homozygotes have been observed.
The variant meets PM2 at supporting level: overall allele frequency is below the 0.1% threshold, though the African subpopulation frequency is borderline (0.112% in v2.1).
Five of six clinical diagnostic laboratories in ClinVar classify this variant as Likely benign or Benign (ClinVar ID 220182), providing supporting evidence for a benign interpretation (BP6_supporting).
Multiple in silico predictors support a benign effect: REVEL score 0.378, BayesDel score -0.243824, and SpliceAI predicts no splicing impact (max delta 0.05). These provide supporting benign evidence (BP4_supporting).
The variant has been observed in multiple individuals in gnomAD presumed to be healthy adults, which is inconsistent with a fully penetrant early-onset dominant disorder such as Gorlin syndrome, providing additional supporting benign evidence (BS2_supporting).
No pathogenic evidence criteria were met: there is no functional data supporting a damaging effect (PS3 not met), no case-control enrichment (PS4 not met), no de novo reports (PS2/PM6 not met), no segregation data (PP1 not met), the variant is not in a known hotspot or critical domain (PM1 not met), and no reputable source reports it as pathogenic (PP5 not met).
No functional studies of p.Arg638His or a systematically characterized range including this residue were identified. The variant has not been experimentally characterized for its effect on Hedgehog signaling, PTCH1-SMO interaction, or protein trafficking.
No criteria match.
Met · 4
PM2 SupportingThis variant is present in gnomAD at very low frequency overall (v2.1: 33/282,644 alleles, AF=0.012%; v4.1: 126/1,613,872 alleles, AF=0.008%), below the 0.1% threshold for PM2. No homozygotes are observed. The African/African American subpopulation AF is 0.112% in v2.1 (borderline above 0.1%) but 0.087% in v4.1, supporting overall rarity. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 overall AF = 0.012% (<0.1%)
- gnomAD v4.1 overall AF = 0.008% (<0.1%)
- Zero homozygotes in both datasets
- African subpopulation AF = 0.112% (v2.1)
- 0.087% (v4.1) — borderline
Still missing
- African subpopulation AF in gnomAD v2.1 (0.112%) is borderline above the 0.1% PM2 cutoff
- may weaken PM2 applicability depending on framework interpretation.
Sources
BS2 SupportingThis variant has been observed in multiple individuals within gnomAD population databases (33 alleles in v2.1, 126 alleles in v4.1) who are presumed healthy adults based on gnomAD's exclusion of severe pediatric disease. Gorlin syndrome is a highly penetrant autosomal dominant disorder with early onset; observation of this variant in population controls at this frequency is consistent with a benign or low-penetrance variant. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 33 heterozygous carriers (0 homozygotes) among 282
- 644 population controls
- gnomAD v4.1: 126 heterozygous carriers (0 homozygotes) among 1
- 613
- 872 population controls
- Gorlin syndrome has high penetrance with early onset
- the variant frequency in controls exceeds the expected pathogenic carrier frequency for this disorder.
Still missing
- Individual phenotypic data for gnomAD carriers are not available
- the assumption of healthy adult status is based on gnomAD cohort design.
Sources
BP4 SupportingMultiple in silico predictors support a benign effect for this variant: REVEL score 0.378 (below the 0.5 pathogenic threshold), BayesDel score -0.243824 (predicting benign), and SpliceAI max delta 0.05 (no predicted splicing impact). These represent multiple independent lines of computational evidence suggesting no functional consequence. Details ▾Hide ▴
Evidence considered
- REVEL score 0.378 (<0.5
- predicting benign)
- BayesDel score -0.243824 (predicting benign)
- SpliceAI max delta 0.05 (no predicted splicing impact)
Sources
BP6 SupportingFive clinical diagnostic laboratories classify this variant as Likely benign (4 labs: GeneDx, Ambry Genetics, Eurofins Ntd, Sema4) or Benign (1 lab: Labcorp Genetics/Invitae) in ClinVar (ClinVar ID 220182). One additional laboratory (ARUP) classifies as VUS. While the review status is 'criteria provided, single submitter' (1-star, below the 3-star expert panel threshold), the consensus across multiple independent clinical laboratories reporting with criteria supports BP6 at supporting benign level. Details ▾Hide ▴
Evidence considered
- ClinVar ID 220182: 5/6 clinical labs classify as Likely benign or Benign
- Labcorp Genetics/Invitae: Benign (SCV000260535
- with criteria
- cites PMID:28492532)
- GeneDx: Likely benign (SCV000730309
- notes conservative change at poorly conserved position)
- Ambry Genetics: Likely benign (SCV001174293
- with criteria)
- Eurofins Ntd: Likely benign (SCV000708880
- Sema4: Likely benign (SCV002526829
- curation method)
- ARUP Laboratories: VUS (SCV000884424
Still missing
- ClinVar review status is 1-star (single submitter per submission)
- no expert panel (3-star) review.
Sources
Not met · 17 · evaluated, threshold not reached
PS1 No evidence identified of a different nucleotide change at c.1913 producing the same p.Arg638His amino acid substitution that has been independently classified as pathogenic. Details ▾Hide ▴
Evidence considered
- No same-amino-acid-change pathogenic variant at this codon identified in ClinVar or the literature.
Still missing
- No systematic screen for alternate nucleotide changes at codon 638 producing p.Arg638His was performed beyond ClinVar and automated PM5 candidate harvesting.
PS2 No de novo occurrence of this variant has been reported with confirmed maternity and paternity testing. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar
- literature
- or submitted case materials.
Still missing
- No parental testing data available.
PS3 No functional data were identified for NM_000264.5:c.1913G>A (p.Arg638His) or for a systematically characterized range that includes this residue. REVEL score 0.378 and BayesDel score -0.243824 do not independently meet PS3 criteria. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- REVEL score 0.378 (below 0.5 pathogenic threshold)
- BayesDel score -0.243824 (predicting benign)
- OncoKB reports Unknown Oncogenic Effect
- no variant-specific functional studies curated
Still missing
- No experimental functional characterization of p.Arg638His has been published.
- No saturation mutagenesis or systematic tiling screen data available for the region spanning residue 638.
Sources
PS4 No case-control data demonstrate enrichment of this variant in affected individuals compared to population controls. The variant is observed in gnomAD population databases at low frequency. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 33/282
- 644 alleles (AF=0.012%)
- gnomAD v4.1: 126/1
- 613
- 872 alleles (AF=0.008%)
Still missing
- No case counts from affected cohorts available.
Sources
PM1 Residue Arg638 does not lie within a statistically significant missense mutation hotspot (cancerhotspots.org). No CSPEC/VCEP-defined critical functional domain mapping assigns this residue to a domain with sufficient specificity to independently satisfy PM1 under generic ACMG/AMP. Details ▾Hide ▴
Evidence considered
- Residue Arg638 is not in a statistically significant hotspot (cancerhotspots.org).
- No CSPEC or custom gene framework defines a critical domain that specifically encompasses Arg638.
Still missing
- PTCH1 domain architecture has not been formally mapped to PM1 criteria for generic ACMG application.
- The residue may fall within a transmembrane or extracellular loop domain
- but domain-level annotation without CSPEC guidance is insufficient for PM1.
PM6 No de novo observation of this variant has been reported without confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in any reviewed source.
Still missing
- No unconfirmed de novo reports available.
PP1 No cosegregation data are available for this variant; no family studies have been reported. Details ▾Hide ▴
Evidence considered
- No family-based segregation studies identified.
Still missing
- No family data available for segregation analysis.
PP2 PTCH1 disease mechanism is primarily loss-of-function, with truncating variants representing the predominant pathogenic variant class. While missense variants in specific functional domains can be pathogenic, the gene has not been established as having a low rate of benign missense variation where missense is the common disease mechanism — prerequisites for PP2. Details ▾Hide ▴
Evidence considered
- PTCH1 LOF mechanism is supported (PVS1 gene gate: eligible).
- Truncating variants are the predominant pathogenic variant class
- missense pathogenicity is domain-dependent.
Still missing
- No gene-specific benign missense constraint metric (e.g.
- missense Z-score) reviewed.
Sources
pvs1_gene_context
PP3 Multiple in silico predictors do not support a damaging effect: REVEL score 0.378 (below commonly used 0.5 pathogenic threshold), BayesDel score -0.243824 (predicting benign), and SpliceAI max delta 0.05 (no predicted splicing impact). No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.378 (<0.5 pathogenic threshold)
- BayesDel score = -0.243824 (benign prediction)
- SpliceAI max delta = 0.05 (no splicing impact)
Sources
PP5 ClinVar classification for this variant is Likely benign (4 clinical laboratories) and Benign (1 clinical laboratory), with one VUS. No reputable source reports this variant as pathogenic. The ClinVar review status is 'criteria provided, single submitter' (1-star), below the 3-star expert panel threshold required for PP5 application. Details ▾Hide ▴
Evidence considered
- ClinVar ID 220182: Likely benign (4 labs)
- Benign (1 lab)
- VUS (1 lab)
- ClinVar review status: criteria provided
- single submitter (1-star)
- No expert panel (3-star) classification available
Sources
BA1 Allele frequency in gnomAD (v2.1: 0.012%; v4.1: 0.008%) is far below the 1% threshold for BA1. This variant is rare, not common. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 0.012% (<<1%)
- gnomAD v4.1 AF = 0.008% (<<1%)
Sources
BS1 The maximum subpopulation allele frequency in gnomAD (African/African American: 0.112% in v2.1, 0.087% in v4.1) is below the 0.3% threshold for BS1. The variant is not observed at a frequency greater than expected for Gorlin syndrome under generic ACMG/AMP criteria. Details ▾Hide ▴
Evidence considered
- Maximum subpopulation AF (African) = 0.112% v2.1
- 0.087% v4.1 (<0.3% BS1 threshold)
- Overall AF = 0.012% v2.1
- 0.008% v4.1
Sources
BS3 No functional studies demonstrating a neutral or benign effect for this variant have been identified. In silico predictions (REVEL 0.378, BayesDel -0.243824) are consistent with a benign effect but do not independently satisfy BS3 criteria, which requires experimental functional evidence. Details ▾Hide ▴
Evidence considered
- No variant-specific experimental functional data available.
- In silico scores are consistent with a benign effect but are not experimental evidence.
Still missing
- No experimental functional characterization (e.g.
- Hedgehog pathway reporter assay
- PTCH1-SMO interaction study) of p.Arg638His has been published.
Sources
BP1 PTCH1 disease mechanism includes both truncating and missense variants. While loss-of-function through truncation is the predominant mechanism, pathogenic missense variants in key functional domains (e.g., sterol-sensing domain, extracellular loops) are well established in Gorlin syndrome. BP1 requires that primarily truncating variants cause disease, which is not clearly satisfied for PTCH1. Details ▾Hide ▴
Evidence considered
- PTCH1 LOF mechanism supported
- but missense variants are also documented as pathogenic in Gorlin syndrome.
- No CSPEC guidance restricting PTCH1 pathogenicity exclusively to truncating variants.
Still missing
- No gene-specific missense constraint analysis reviewed.
Sources
pvs1_gene_context
BP2 No evidence that this variant has been observed in trans with a known pathogenic PTCH1 variant, or in cis with a pathogenic variant in any inheritance pattern. Details ▾Hide ▴
Evidence considered
- No reports of this variant in trans or cis with another PTCH1 pathogenic variant.
Still missing
- No phasing data or multi-variant genotype data available.
BP5 No case has been identified in which this variant is observed in an individual with an alternate molecular explanation for the phenotype. BP5 requires a specific case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No case with alternate molecular basis identified.
Still missing
- No co-occurring variant data in affected individuals available.
PS5 No de novo occurrence of this variant has been reported in the literature or ClinVar submissions, with or without confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in any reviewed source.
Still missing
- No trio sequencing data available.
Not assessed · 2 · no assessment recorded
PP4 No patient phenotype or clinical history was provided for this assessment. PP4 requires evaluation of whether the patient's phenotype or family history is specific for PTCH1-associated disease (Gorlin syndrome / NBCCS). Details ▾Hide ▴
Evidence considered
- No patient clinical data available in the case materials.
Still missing
- Patient phenotype
- family history
- and clinical presentation not provided.
BS4 No family-based segregation data are available to evaluate lack of segregation with disease. BS4 requires observation that the variant does not segregate with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family studies or segregation analysis available for this variant.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000264.5:c.1913G>A is a missense variant (p.Arg638His) and does not fall into generic PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). The PVS1 generic framework was not applied. Details ▾Hide ▴
Evidence considered
- Variant is a substitution at c.1913 producing p.Arg638His
- classified as 'other' in the PVS1 variant bucket assessment.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/APTCH1-associated disorders (Gorlin syndrome / NBCCS) are autosomal dominant; PM3 applies to recessive disorders requiring a pathogenic variant in trans. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AVariant is a single nucleotide missense substitution and does not alter protein length via stop-loss, in-frame deletion/insertion, or initiation codon change. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo pathogenic missense variant at the same amino acid residue (Arg638) was identified in ClinVar. Automated PM5 candidate harvesting returned zero same-residue comparators; classic PM5 semantics could not be confirmed. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvest found zero same-residue pathogenic missense variants at p.Arg638.
Sources
pm5_candidates
BP3 N/AVariant is a missense substitution, not an in-frame insertion or deletion. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AVariant is a missense substitution (c.1913G>A, p.Arg638His), not a synonymous/silent variant. BP7 is reserved for synonymous variants at non-conserved positions without splicing impact. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
- SpliceAI max delta 0.05 confirms no cryptic splicing impact
- but BP7 criteria are specifically for synonymous variants.
Sources
Identifiers
- Gene
- PTCH1
- Transcript
- NM_000264.5
- Coding (HGVS c.)
- NM_000264.5:c.1913G>A
- Protein (HGVS p.)
- NP_000255.2:p.(Arg638His)
- GRCh38
- chr9:95469088 C>T
- GRCh37
- chr9:98231370 C>T
- ClinVar
- 2118120, 220182
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
126 / 1,613,872 alleles
AF 7.81e-05 · 0 homozygotes · FAF 0.000698
gnomAD v2.1
33 / 282,644 alleles
AF 0.000117 · 0 homozygotes · FAF 0.00102
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 7.8e-05 · 126 / 1,613,872 alleles · 0 hom · FAF 0.0007
| African/African American65 / 74,956 | 0.00087 |
| Middle Eastern1 / 6,062 | 0.00016 |
| Admixed American6 / 59,996 | 0.0001 |
| Remaining individuals4 / 62,508 | 6.4e-05 |
| European (non-Finnish)49 / 1,179,998 | 4.2e-05 |
| East Asian1 / 44,870 | 2.2e-05 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00012 · 33 / 282,644 alleles · 0 hom · FAF 0.001
| African/African American28 / 24,952 | 0.0011 |
| Remaining individuals1 / 7,222 | 0.00014 |
| Admixed American3 / 35,440 | 8.5e-05 |
| European (non-Finnish)1 / 129,086 | 7.7e-06 |
0 alternate alleles recorded in 4 other groups: Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 7.80731e-05; MAF= 0.00781%, 126/1613872 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000867175; MAF= 0.08672%, 65/74956 alleles, homozygotes = 0); grpmax FAF= 0.0006979.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000116755; MAF= 0.01168%, 33/282644 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00112215; MAF= 0.11222%, 28/24952 alleles, homozygotes = 0); grpmax FAF= 0.00101842.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.378
- BayesDel
- -0.244
How the predictions were used
BP4 SupportingMultiple in silico predictors support a benign effect for this variant: REVEL score 0.378 (below the 0.5 pathogenic threshold), BayesDel score -0.243824 (predicting benign), and SpliceAI max delta 0.05 (no predicted splicing impact). These represent multiple independent lines of computational evidence suggesting no functional consequence. Details ▾Hide ▴
Evidence considered
- REVEL score 0.378 (<0.5
- predicting benign)
- BayesDel score -0.243824 (predicting benign)
- SpliceAI max delta 0.05 (no predicted splicing impact)
Sources
PP3 Multiple in silico predictors do not support a damaging effect: REVEL score 0.378 (below commonly used 0.5 pathogenic threshold), BayesDel score -0.243824 (predicting benign), and SpliceAI max delta 0.05 (no predicted splicing impact). No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.378 (<0.5 pathogenic threshold)
- BayesDel score = -0.243824 (benign prediction)
- SpliceAI max delta = 0.05 (no splicing impact)
Sources
BP7 N/AVariant is a missense substitution (c.1913G>A, p.Arg638His), not a synonymous/silent variant. BP7 is reserved for synonymous variants at non-conserved positions without splicing impact. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
- SpliceAI max delta 0.05 confirms no cryptic splicing impact
- but BP7 criteria are specifically for synonymous variants.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.378. BayesDel score = -0.243824.
6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004National Society of Genetic Counselors practice recommendations for cancer genetic counseling and risk assessment. This is a guideline document with no variant-specific content.Does not name this variant
-
PMID 21304560 ↗Clinical utility gene card for: Gorlin syndrome.Lo Muzio L et al. · 2011Clinical utility gene card for Gorlin syndrome published in European Journal of Human Genetics. Reviews PTCH1 as the major gene for Gorlin syndrome at a gene level.Does not name this variant
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. Recommends criteria for referral to cancer genetics services.Does not name this variant
-
PMID 26389210 ↗Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ cancer genetics summary covering hereditary breast and gynecologic cancer syndromes. PTCH1 is not a focus of this summary.Does not name this variant
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ cancer genetics summary on cancer risk assessment and counseling. General overview of cancer genetics practice.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Sherloc classification framework paper describing refinement of ACMG-AMP variant classification criteria. Referenced by the Labcorp Genetics/Invitae ClinVar submission (SCV000260535) as the methodological basis for their Benign classification of this variant.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
126 / 1,613,872 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.050
Open source ↗
ClinVar
4 Likely benign · 1 Benign · 1 Uncertain significance
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/variation/220182/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-98231370-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-95469088-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-95469088-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000264.5%3Ac.1913…
- OncoKB ↗www.oncokb.org/gene/PTCH1/R638H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PTCH1+c.1913G%3EA
- 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
This variant is present in gnomAD v4.1 (AF= 7.80731e-05; MAF= 0.00781%, 126/1613872 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000867175; MAF= 0.08672%, 65/74956 alleles, homozygotes = 0); grpmax FAF= 0.0006979.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000116755; MAF= 0.01168%, 33/282644 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00112215; MAF= 0.11222%, 28/24952 alleles, homozygotes = 0); grpmax FAF= 0.00101842.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 220182)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.378. BayesDel score = -0.243824.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.