About PTCH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTCH1 c.431G>A, p.(Arg144His)
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is exceedingly rare in population databases: gnomAD v2.1 allele frequency = 3.98e-6 (1/251,480 alleles), gnomAD v4.1 AF = 4.34e-6 (7/1,614,112 alleles), both well below the 0.1% (0.001) threshold. No homozygotes have been observed.
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; combination = 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
7 / 1,614,112 alleles
gnomAD v4.1: 7 / 1,614,112 alleles. Recorded AF 4.33675e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97646e-06; MAF= 0.00040%, 1/251480 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89084e-05; MAF= 0.00289%, 1/34592 alleles, homozygotes = 0).
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.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
4 reported laboratory submissions
3 Uncertain significance · 1 Likely benign.
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
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV59469010, n = 2 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: 1 met · 23 not met · 0 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(PTCH1):c.431G>A (p.Arg144His) is a missense variant in PTCH1, a gene associated with autosomal dominant Gorlin syndrome (nevoid basal cell carcinoma syndrome).
This variant is exceedingly rare in population databases, with an allele frequency of approximately 4.0e-6 in both gnomAD v2.1 (1/251,480 alleles) and v4.1 (7/1,614,112 alleles), and no homozygotes have been observed.
The variant has been reported in ClinVar (Variation ID 575795) as Uncertain Significance by three clinical laboratories and as Likely Benign by one laboratory; no expert panel classification is available.
Computational predictors are mixed: REVEL scores 0.583 (borderline), BayesDel scores 0.231 (benign-leaning), and SpliceAI predicts no splicing impact (max delta 0.05).
No variant-specific functional studies, segregation data, de novo observations, case-control data, or reputable pathogenic classifications are available for this variant.
Applying generic ACMG/AMP 2015 criteria (PMID:25741868), only PM2 (supporting) is met. With a single supporting pathogenic criterion and no benign criteria met, the final classification is a Variant of Uncertain Significance.
No criteria match.
Met · 1
PM2 SupportingThis variant is exceedingly rare in population databases: gnomAD v2.1 allele frequency = 3.98e-6 (1/251,480 alleles), gnomAD v4.1 AF = 4.34e-6 (7/1,614,112 alleles), both well below the 0.1% (0.001) threshold. No homozygotes have been observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF = 3.98e-6 (1/251
- 480 alleles
- 0 homozygotes)
- gnomAD v4.1: AF = 4.34e-6 (7/1
- 614
- 112 alleles
Sources
Not met · 23 · evaluated, threshold not reached
PS1 No different nucleotide change resulting in p.Arg144His has been reported as pathogenic in ClinVar or the literature reviewed for this case. Details ▾Hide ▴
Evidence considered
- ClinVar variation 575795 shows only this nucleotide change (c.431G>A) at Arg144
- no alternative nucleotide substitution leading to R144H with a pathogenic classification was identified.
Still missing
- No comparator nucleotide changes at Arg144 cataloged.
Sources
PS2 No de novo occurrence data (with confirmed maternity/paternity) are available for this variant. Reviewed publications contain no variant-specific de novo reports. Details ▾Hide ▴
Still missing
- No de novo data from clinical or research settings.
Sources
257418682849253225394175156046282030133021304560263893332638921026389258
PS3 No well-established in vitro or in vivo functional studies demonstrating a damaging effect on PTCH1 for this specific variant are available. OncoKB reports unknown oncogenic effect, and none of the reviewed publications contain variant-specific functional assay data. Details ▾Hide ▴
Evidence considered
- OncoKB classifies this variant as Unknown Oncogenic Effect
- no variant-specific functional evidence identified in reviewed literature.
Still missing
- No functional assay data for p.Arg144His in PTCH1.
Sources
PS4 No case-control or odds-ratio data comparing variant prevalence in affected versus unaffected individuals are available. Reviewed publications are general practice guidelines, PDQ summaries, and methodology papers that do not provide variant-specific observational data. Details ▾Hide ▴
Evidence considered
- No enriched prevalence in cases versus controls demonstrated.
Still missing
- No case-control or cohort study with this variant.
Sources
257418682849253225394175156046282030133021304560263893332638921026389258
PM1 Arg144 is not located in a statistically significant mutational hotspot for PTCH1. Independent evidence localizing codon 144 to a critical and well-established functional domain was not available in the evidence record. Details ▾Hide ▴
Evidence considered
- Hotspot analysis result: residue not significant
- exact variant not listed in any statistically significant hotspot.
Still missing
- No domain-level functional annotation mapping for PTCH1 codon 144 in the evidence record.
PM5 No different missense change at Arg144 (p.Arg144Gly, p.Arg144Cys, etc.) has been established as pathogenic. Automated PM5 comparator candidate harvesting returned no eligible comparators. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: total candidates seen = 0
- same-residue candidates = 0.
Still missing
- No same-residue pathogenic missense comparators identified.
Sources
pm5_candidates
PM6 No de novo occurrence data (without confirmation of paternity/maternity) are available for this variant. Reviewed literature contains no de novo reports. Details ▾Hide ▴
Still missing
- No de novo reports in clinical or research literature.
Sources
257418682849253225394175156046282030133021304560263893332638921026389258
PP1 No segregation data demonstrating co-segregation of this variant with disease in multiple affected family members are available. Details ▾Hide ▴
Still missing
- No family-based segregation analysis available.
PP2 Although PTCH1 missense variants are a well-established disease mechanism in Gorlin syndrome, gene-level missense constraint metrics (e.g., gnomAD missense Z-score, regional constraint) were not available in the evidence record to establish a low rate of benign missense variation, which is required to meet PP2 under generic ACMG/AMP criteria. Details ▾Hide ▴
Evidence considered
- PTCH1 is associated with Gorlin syndrome
- missense variants are a known disease mechanism. However
- constraint metrics to demonstrate a low rate of benign missense variation are absent from the evidence record.
Still missing
- gnomAD missense constraint metrics (Z-score
- o/e) not available in evidence record.
PP3 Computational evidence is mixed and does not provide multiple concordant lines supporting a deleterious effect. REVEL = 0.583 (borderline, below typical high-confidence pathogenic thresholds), BayesDel = 0.231 (benign-leaning), and SpliceAI max delta = 0.05 (no predicted splicing impact). A single borderline REVEL score does not constitute multiple lines of computational support. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.583 (borderline)
- BayesDel score: 0.231 (benign-leaning)
- SpliceAI max delta: 0.05 (no splicing impact)
Sources
PP4 Insufficient clinical phenotypic specificity is documented for the patient(s) carrying this variant. No detailed phenotype description highly specific for Gorlin syndrome with a single genetic etiology is available in the evidence record. Details ▾Hide ▴
Still missing
- No detailed patient phenotype data available
- ClinVar submissions lack condition labels in the evidence record.
PP5 No reputable source (e.g., expert panel, clinical laboratory with published strong evidence) has reported this variant as pathogenic. ClinVar reports three submitters as VUS and one as Likely Benign. The cited PMIDs (25741868, 28492532) are general classification methodology papers that do not assess this variant specifically. Details ▾Hide ▴
Evidence considered
- ClinVar variation 575795: VUS (3 clinical laboratories)
- LB (1 clinical laboratory).
- PMID:25741868 (Richards 2015) and PMID:28492532 (Nykamp 2017) are classification methodology papers
- neither assesses c.431G>A.
Sources
BA1 gnomAD allele frequency (~4e-6) is far below the >1% BA1 threshold. This variant is extremely rare, not common. Details ▾Hide ▴
BS1 gnomAD allele frequency (~4e-6) is far below the >0.3% BS1 threshold. This variant is extremely rare, not a benign-standing polymorphism. Details ▾Hide ▴
BS2 No homozygotes for this variant have been observed in gnomAD. For a fully penetrant dominant condition (Gorlin syndrome), BS2 requires observation in a healthy adult homozygous state, which is not present. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0 homozygotes
- gnomAD v4.1: 0 homozygotes
Sources
BS3 No well-established functional studies demonstrating no damaging effect for this specific variant are available. OncoKB reports unknown oncogenic effect with no variant-specific functional data. Details ▾Hide ▴
Evidence considered
- No variant-specific benign functional data identified in OncoKB or reviewed literature.
Still missing
- No functional assay data available for p.Arg144His.
Sources
BS4 No segregation data are available to evaluate lack of segregation of this variant with disease in affected family members. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP1 PTCH1 is not a gene where primarily truncating variants cause disease. Pathogenic missense variants in PTCH1 are a well-established mechanism of Gorlin syndrome, as supported by the germline disease literature reviewed in the PVS1 gene-level context. Details ▾Hide ▴
Evidence considered
- PTCH1 missense variants are a known cause of Gorlin syndrome
- BP1 does not apply.
Sources
pvs1_gene_context408810544188881941816662
BP2 No data are available regarding the occurrence of this variant in trans with a known pathogenic variant (relevant for recessive disorders) or in cis with a pathogenic variant. Additionally, Gorlin syndrome is an autosomal dominant condition. Details ▾Hide ▴
Still missing
- No cis/trans phase data available.
BP4 Computational evidence is mixed and does not provide multiple concordant lines of evidence suggesting no impact. REVEL = 0.583 is in a pathogenic-leaning range, BayesDel = 0.231 is benign-leaning but not strongly so. SpliceAI shows no splicing impact, but this does not constitute multiple lines of benign computational evidence. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.583 (pathogenic-leaning
- does not support no impact)
- BayesDel score: 0.231 (benign-leaning)
- SpliceAI max delta: 0.05 (no splicing impact)
Sources
BP5 No evidence is available that a case harboring this variant has an alternate molecular basis for disease. BP5 requires identification of an alternative causative variant in a proband with this variant. Details ▾Hide ▴
Still missing
- No data on alternative molecular diagnoses in carriers.
BP6 Although Labcorp Genetics (Invitae) classifies this variant as Likely Benign (SCV000826756), the evidence supporting that classification is not available for independent evaluation. BP6 requires a reputable source (typically an expert panel or multiple laboratories with strong consensus) to report the variant as benign with evidence not independently available. A single clinical laboratory submission citing only a general classification methodology paper (PMID:28492532, Sherloc) does not meet this threshold. Details ▾Hide ▴
Evidence considered
- ClinVar SCV000826756: Likely Benign from Labcorp Genetics
- citing PMID:28492532 (Sherloc methodology paper).
- PMID:28492532 does not contain variant-specific evidence for c.431G>A.
Still missing
- Specific evidence underlying the Labcorp LB classification is not publicly available.
Sources
PS5 No different missense change at Arg144 has been established as pathogenic. Automated PM5 comparator candidate harvesting returned no candidates at this residue. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned zero same-residue comparators with pathogenic classification.
Still missing
- No missense comparator at Arg144 with established pathogenicity.
Sources
pm5_candidates
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/Ac.431G>A (p.Arg144His) is a missense variant. PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, or exon-level deletions). This variant falls into the 'other' variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798) and does not meet any default null-variant criteria. Details ▾Hide ▴
Evidence considered
- Missense variant at codon 144
- no canonical splice disruption
- not a null variant category.
Sources
PM3 N/APTCH1-associated Gorlin syndrome is an autosomal dominant disorder. PM3 (variant in trans with a pathogenic variant) applies to recessive disorders. Details ▾Hide ▴
Evidence considered
- Autosomal dominant inheritance
- PM3 is reserved for recessive disorders.
PM4 N/Ac.431G>A is a single-nucleotide missense substitution, not a protein-length-altering variant (in-frame deletion/insertion or stop-loss). Details ▾Hide ▴
Evidence considered
- Missense substitution
- not an in-frame indel or stop-loss variant.
BP3 N/Ac.431G>A is a single-nucleotide substitution, not an in-frame indel. BP3 applies to in-frame deletions/insertions in a repetitive region without a known function. Details ▾Hide ▴
Evidence considered
- Substitution variant
- not an in-frame indel.
BP7 N/Ac.431G>A is a missense variant (p.Arg144His), not a synonymous (silent) variant. BP7 is reserved for synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous.
Identifiers
- Gene
- PTCH1
- Transcript
- NM_000264.5
- Coding (HGVS c.)
- NM_000264.5:c.431G>A
- Protein (HGVS p.)
- NP_000255.2:p.(Arg144His)
- GRCh38
- chr9:95485838 C>T
- GRCh37
- chr9:98248120 C>T
- ClinVar
- 575795
- COSMIC
- COSV59469010
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in PTCH1
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
7 / 1,614,112 alleles
AF 4.34e-06 · 0 homozygotes · FAF 2.47e-06
gnomAD v2.1
1 / 251,480 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 4.3e-06 · 7 / 1,614,112 alleles · 0 hom · FAF 2.5e-06
| European (non-Finnish)7 / 1,180,032 | 5.9e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 251,480 alleles · 0 hom
| Admixed American1 / 34,592 | 2.9e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.33675e-06; MAF= 0.00043%, 7/1614112 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.93204e-06; MAF= 0.00059%, 7/1180032 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97646e-06; MAF= 0.00040%, 1/251480 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89084e-05; MAF= 0.00289%, 1/34592 alleles, homozygotes = 0).
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.583
- BayesDel
- 0.231
How the predictions were used
PP3 Computational evidence is mixed and does not provide multiple concordant lines supporting a deleterious effect. REVEL = 0.583 (borderline, below typical high-confidence pathogenic thresholds), BayesDel = 0.231 (benign-leaning), and SpliceAI max delta = 0.05 (no predicted splicing impact). A single borderline REVEL score does not constitute multiple lines of computational support. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.583 (borderline)
- BayesDel score: 0.231 (benign-leaning)
- SpliceAI max delta: 0.05 (no splicing impact)
Sources
BP4 Computational evidence is mixed and does not provide multiple concordant lines of evidence suggesting no impact. REVEL = 0.583 is in a pathogenic-leaning range, BayesDel = 0.231 is benign-leaning but not strongly so. SpliceAI shows no splicing impact, but this does not constitute multiple lines of benign computational evidence. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.583 (pathogenic-leaning
- does not support no impact)
- BayesDel score: 0.231 (benign-leaning)
- SpliceAI max delta: 0.05 (no splicing impact)
Sources
BP7 N/Ac.431G>A is a missense variant (p.Arg144His), not a synonymous (silent) variant. BP7 is reserved for synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.583. BayesDel score = 0.230949.
9 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 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015No paper-specific finding is recorded.
-
PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004No paper-specific finding is recorded.
-
PMID 20301330 ↗Nevoid Basal Cell Carcinoma Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
-
PMID 21304560 ↗Clinical utility gene card for: Gorlin syndrome.Lo Muzio L et al. · 2011No paper-specific finding is recorded.
-
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. · 2015No paper-specific finding is recorded.
-
PMID 26389210 ↗Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002No paper-specific finding is recorded.
-
PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002No paper-specific finding is recorded.
-
PMID 26389333 ↗Genetics of Skin Cancer (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
7 / 1,614,112 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
3 Uncertain significance · 1 Likely benign
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/575795/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-98248120-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-95485838-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-95485838-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000264.5%3Ac.431G…
- OncoKB ↗www.oncokb.org/gene/PTCH1/R144H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=127883699
- 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= 4.33675e-06; MAF= 0.00043%, 7/1614112 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.93204e-06; MAF= 0.00059%, 7/1180032 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97646e-06; MAF= 0.00040%, 1/251480 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89084e-05; MAF= 0.00289%, 1/34592 alleles, homozygotes = 0).
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 575795)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.583. BayesDel score = 0.230949.
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; COSV59469010, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.