About PTCH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTCH1 c.1641C>T, p.(Ser547=)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A 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
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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: 0
Benign evidence criteria: 6
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 6
BA1Stand alone
BA1 · stand alone
NM_000264.5:c.1641C>T has an allele frequency exceeding 1% in gnomAD. In v4.1 the total AF is 1.125% (18153/1613520 alleles) and the grpmax FAF is 1.38%. In v2.1 the European (non-Finnish) subpopulation AF is 1.37% (1756/128296 alleles) and the grpmax FAF is 1.32%. These frequencies exceed the BA1 >1% threshold and are incompatible with a highly penetrant autosomal dominant disorder (Gorlin syndrome).
BS1Strong
BS1 · strong
NM_000264.5:c.1641C>T has an allele frequency exceeding 0.3% in gnomAD. In v2.1 the total AF is 0.798% (2242/281002 alleles) and in v4.1 the total AF is 1.125% (18153/1613520 alleles). These frequencies are substantially above the 0.3% BS1 threshold for a highly penetrant dominant disorder.
BS2Strong
BS2 · strong
NM_000264.5:c.1641C>T has been observed in the homozygous state in multiple individuals in gnomAD: 17 homozygotes in v2.1 and 125 homozygotes in v4.1. For a fully penetrant autosomal dominant disorder (Gorlin syndrome), the presence of healthy adult homozygotes in population databases is strong evidence for a benign classification.
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splicing impact (max delta score=0.00 for all acceptor and donor gain/loss predictions). This is a synonymous variant (p.Ser547=) at a position where no splicing disruption is predicted. While REVEL and BayesDel scores are unavailable, the absence of any in silico evidence of deleteriousness supports a benign interpretation.
BP6Supporting
BP6 · supporting
A reputable source (ClinVar) classifies NM_000264.5:c.1641C>T as Benign. Fourteen clinical laboratories have submitted Benign classifications, with one additional likely benign and one additional benign submission. While no expert panel has reviewed this variant, the consistent classification across multiple clinical laboratories provides supporting evidence for a benign interpretation.
BP7Supporting
BP7 · supporting
NM_000264.5:c.1641C>T is a synonymous variant (p.Ser547=) at a nucleotide position with no predicted splicing impact. SpliceAI predicts a max delta score of 0.00, indicating the variant does not alter any splice site. In the absence of evidence for an effect on splicing, synonymous variants are generally considered likely benign under BP7.
Recorded classification: 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: BA1 stand-alone benign, BS1 strong benign, BS2 strong benign, BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; combination = 1 stand-alone benign + 2 strong benign + 3 supporting benign, which maps to 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
18,153 / 1,613,520 alleles
gnomAD v4.1: 18,153 / 1,613,520 alleles. Recorded AF 0.0112506. Recorded homozygote count 125.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00797859; MAF= 0.79786%, 2242/281002 alleles, homozygotes = 17) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0136871; MAF= 1.36871%, 1756/128296 alleles, homozygotes = 14); grpmax FAF= 0.0131535.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.006785365324069048, 125/18422 alleles, homozygotes = 0).
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
16 reported laboratory submissions
14 Benign · 1 Likely benign · 1 benign.
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
5 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV59461249, n = 5 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.
27 criteria with recorded statuses: 6 met · 6 not met · 9 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
NM_000264.5:c.1641C>T is a synonymous variant (p.Ser547=) in PTCH1 with no predicted impact on splicing (SpliceAI max delta=0.00).
This variant is present at high frequency in population databases: gnomAD v2.1 AF=0.798% (2242/281002 alleles, including 17 homozygotes) and v4.1 AF=1.125% (18153/1613520 alleles, including 125 homozygotes), exceeding the BA1 (>1%) and BS1 (>0.3%) thresholds for an autosomal dominant disorder with full penetrance expected at an early age.
The observation of 17 homozygotes in gnomAD v2.1 and 125 homozygotes in gnomAD v4.1 is incompatible with a fully penetrant autosomal dominant condition; this alone is strong evidence for a benign classification (BS2).
ClinVar classifies this variant as Benign based on submissions from 14 clinical laboratories; this represents a reputable source reporting a benign classification (BP6).
The variant was identified as a non-pathogenic synonymous polymorphism (rs2066830, p.S547S) in a study of 78 sporadic medulloblastoma cases and in ovarian tumor/control cohorts, consistent with a benign interpretation.
Computational evidence (SpliceAI) predicts no splicing impact; combined with its synonymous nature, this supports a benign interpretation (BP4, BP7).
The BA1 criterion is met at stand-alone benign strength: allele frequency >1% in multiple gnomAD populations is incompatible with a highly penetrant dominant disorder. Per ACMG/AMP 2015 combination rules, meeting BA1 alone is sufficient for a Benign classification regardless of other criteria.
No criteria match.
Met · 6
BA1 Stand aloneNM_000264.5:c.1641C>T has an allele frequency exceeding 1% in gnomAD. In v4.1 the total AF is 1.125% (18153/1613520 alleles) and the grpmax FAF is 1.38%. In v2.1 the European (non-Finnish) subpopulation AF is 1.37% (1756/128296 alleles) and the grpmax FAF is 1.32%. These frequencies exceed the BA1 >1% threshold and are incompatible with a highly penetrant autosomal dominant disorder (Gorlin syndrome). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: total AF=1.125%
- grpmax FAF=1.38%
- gnomAD v2.1: NFE subpopulation AF=1.37%
- grpmax FAF=1.32%. All exceed the 1% BA1 threshold for a dominant disorder with full penetrance expected at an early age.
Sources
BS1 StrongNM_000264.5:c.1641C>T has an allele frequency exceeding 0.3% in gnomAD. In v2.1 the total AF is 0.798% (2242/281002 alleles) and in v4.1 the total AF is 1.125% (18153/1613520 alleles). These frequencies are substantially above the 0.3% BS1 threshold for a highly penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: total AF=0.798%
- gnomAD v4.1: total AF=1.125%. Both far exceed the 0.3% BS1 threshold.
Sources
BS2 StrongNM_000264.5:c.1641C>T has been observed in the homozygous state in multiple individuals in gnomAD: 17 homozygotes in v2.1 and 125 homozygotes in v4.1. For a fully penetrant autosomal dominant disorder (Gorlin syndrome), the presence of healthy adult homozygotes in population databases is strong evidence for a benign classification. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 17 homozygotes
- gnomAD v4.1: 125 homozygotes. Homozygous state incompatible with a fully penetrant dominant disorder.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splicing impact (max delta score=0.00 for all acceptor and donor gain/loss predictions). This is a synonymous variant (p.Ser547=) at a position where no splicing disruption is predicted. While REVEL and BayesDel scores are unavailable, the absence of any in silico evidence of deleteriousness supports a benign interpretation. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta=0.00
- no predicted acceptor gain/loss or donor gain/loss. Synonymous substitution with no predicted impact on splicing or protein sequence.
Sources
BP6 SupportingA reputable source (ClinVar) classifies NM_000264.5:c.1641C>T as Benign. Fourteen clinical laboratories have submitted Benign classifications, with one additional likely benign and one additional benign submission. While no expert panel has reviewed this variant, the consistent classification across multiple clinical laboratories provides supporting evidence for a benign interpretation. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 132700: Benign (14 clinical laboratories)
- Likely benign (1)
- benign (1). Overall classification: Benign. Review status: criteria provided
- single submitter.
Sources
BP7 SupportingNM_000264.5:c.1641C>T is a synonymous variant (p.Ser547=) at a nucleotide position with no predicted splicing impact. SpliceAI predicts a max delta score of 0.00, indicating the variant does not alter any splice site. In the absence of evidence for an effect on splicing, synonymous variants are generally considered likely benign under BP7. Details ▾Hide ▴
Evidence considered
- Synonymous variant (p.Ser547=)
- SpliceAI max delta=0.00 (no predicted splicing impact). No cryptic splice site creation or loss predicted.
Sources
Not met · 6 · evaluated, threshold not reached
PS4 The variant is common in the general population (gnomAD v2.1 AF=0.798%, v4.1 AF=1.125%) and is classified as Benign in ClinVar. There is no evidence of statistically significant enrichment in affected individuals versus controls. In PMID:23313819, the variant was observed in dermoid and control samples but not enriched in ovarian tumors. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.798% (2242/281002 alleles)
- gnomAD v4.1: AF=1.125% (18153/1613520 alleles)
- ClinVar: Benign (14 labs). PMID:23313819: variant found in dermoid samples and healthy controls (MAF 3.3%)
- not enriched in ovarian carcinomas or fibromas.
Sources
PM1 The variant does not lie within a statistically significant mutational hotspot (residue_significant=false) and no critical functional domain without benign variation has been identified for this position. The PTCH1 hotspots analysis confirms the variant is not in a known hotspot. Details ▾Hide ▴
Evidence considered
- Hotspots analysis: residue_significant=false
- exact_variant_listed='no'. The variant lies in exon 12
- a region not identified as a statistically significant hotspot.
PM2 PM2 requires absence from population controls (or AF <0.1% in non-VCEP framework). NM_000264.5:c.1641C>T is present in gnomAD v2.1 at AF=0.798% (2242/281002 alleles, 17 homozygotes) and v4.1 at AF=1.125% (18153/1613520 alleles, 125 homozygotes), far exceeding the 0.1% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.798% (exceeds PM2 0.1% threshold)
- gnomAD v4.1: AF=1.125% (exceeds PM2 0.1% threshold).
Sources
PP3 Multiple lines of computational evidence do NOT support a deleterious effect. SpliceAI predicts no splicing impact (max delta=0.00). REVEL and BayesDel scores are unavailable. This is a synonymous variant with no in silico evidence of functional disruption. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta score=0.00 (no predicted splicing impact for any acceptor/donor gain or loss). REVEL: not found. BayesDel: not found. No computational tool predicts a deleterious effect for this synonymous variant.
Sources
PP5 Reputable sources do not report NM_000264.5:c.1641C>T as pathogenic. ClinVar classifies the variant as Benign (14 clinical laboratories). PMID:21188540 explicitly lists this variant among non-pathogenic synonymous PTCH1 variants. Details ▾Hide ▴
Evidence considered
- ClinVar: Benign (14 clinical laboratories
- plus 1 likely benign
- 1 benign). PMID:21188540: c.1641C>T explicitly classified as a non-pathogenic synonymous variant in a study of 78 sporadic medulloblastoma cases.
Sources
PS5 No reputable source reports NM_000264.5:c.1641C>T as pathogenic. ClinVar classifies this variant as Benign (14 clinical laboratories), and PMID:21188540 explicitly lists it among non-pathogenic PTCH1 variants. Details ▾Hide ▴
Evidence considered
- ClinVar: Benign (14 labs
- 1 likely benign
- 1 benign)
- PMID:21188540: c.1641C>T (rs2066830
- p.S547S) classified as a non-pathogenic synonymous variant.
Sources
Not assessed · 9 · no assessment recorded
PS2 No de novo observation (with confirmed paternity and maternity) has been reported for NM_000264.5:c.1641C>T in the reviewed literature. Details ▾Hide ▴
Evidence considered
- PMID:29498494 reports a de novo PTCH1 mutation (c.3364_3365delAT) in twins but the family was wild-type for c.1641C>T (rs2066830). No de novo report exists for c.1641C>T itself.
Still missing
- No de novo report identified for this variant.
PS3 No well-established in vitro or in vivo functional studies were identified that directly assess the functional impact of NM_000264.5:c.1641C>T. Details ▾Hide ▴
Evidence considered
- No variant-specific functional studies identified in the reviewed literature. The variant is synonymous and SpliceAI predicts no splicing impact (max delta=0.00).
Still missing
- No variant-specific functional data available.
PM6 No de novo observation (without confirmation of paternity and maternity) has been reported for NM_000264.5:c.1641C>T. Details ▾Hide ▴
Evidence considered
- No de novo report for c.1641C>T identified. PMID:29498494 describes a de novo PTCH1 mutation (c.3364_3365delAT) but the family was wild-type for c.1641C>T.
Still missing
- No de novo evidence for this specific variant.
PP1 No co-segregation data for NM_000264.5:c.1641C>T with disease in affected families was identified in the reviewed literature. Details ▾Hide ▴
Evidence considered
- PMID:21188540 reports family-based sequencing of PTCH1 but c.1641C>T was classified as non-pathogenic. No segregation evidence supporting pathogenicity identified.
Still missing
- No segregation data identified for this variant.
PP4 No specific patient phenotype data were available for NM_000264.5:c.1641C>T to assess whether the patient's phenotype or family history is highly specific for PTCH1-related disease. Details ▾Hide ▴
Evidence considered
- No case-level phenotype data for patients harboring this variant were available in the reviewed sources.
Still missing
- No specific patient phenotype data available.
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect were identified for NM_000264.5:c.1641C>T specifically. The variant is synonymous and computational evidence (SpliceAI delta=0.00) suggests no splicing impact, which is consistent with a benign interpretation but does not constitute the well-established functional evidence required for BS3. Details ▾Hide ▴
Evidence considered
- SpliceAI predicts no splicing impact (max delta=0.00)
- consistent with a benign interpretation. No variant-specific functional assay data were identified in the reviewed literature.
Still missing
- No variant-specific functional assay data available.
Sources
BS4 No family-based lack of segregation data were identified for NM_000264.5:c.1641C>T. The available literature (PMID:21188540, PMID:29498494) does not report segregation analysis for this specific variant. Details ▾Hide ▴
Evidence considered
- No segregation data for c.1641C>T identified. PMID:21188540 classified this variant as non-pathogenic but does not provide formal segregation analysis.
Still missing
- No segregation data for this variant.
BP2 No data were identified showing NM_000264.5:c.1641C>T observed in trans with a known pathogenic PTCH1 variant. PTCH1-related disorders are autosomal dominant, making trans configuration less relevant, but BP2 was not formally assessed due to absence of co-occurrence data. Details ▾Hide ▴
Evidence considered
- No co-occurrence data with pathogenic PTCH1 variants identified in the reviewed sources.
Still missing
- No trans co-occurrence data available.
BP5 No case with an alternate molecular basis for disease was identified that harbors NM_000264.5:c.1641C>T. No evidence was found of this variant occurring in a patient whose phenotype is explained by a different pathogenic variant. Details ▾Hide ▴
Evidence considered
- No data identified showing c.1641C>T in a case with an alternate confirmed molecular diagnosis.
Still missing
- No co-occurrence data with an alternate molecular basis.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 applies to null variants (nonsense, frameshift, canonical ±1,2 splice sites). NM_000264.5:c.1641C>T is a synonymous variant (p.Ser547=) and does not fall into any PVS1 null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Synonymous substitution with no predicted loss-of-function mechanism
- PVS1 variant assessment confirms variant_bucket='other'
- apply_generic_pvs1_framework=false.
Sources
PS1 N/APS1 requires the same amino acid change as a previously established pathogenic variant. c.1641C>T is a synonymous variant with no amino acid change (p.Ser547=). Details ▾Hide ▴
Evidence considered
- Synonymous variant
- no amino acid change exists to compare against known pathogenic missense variants.
PM5 N/APM5 requires a different missense change at the same residue as a known pathogenic missense variant. c.1641C>T is a synonymous variant producing no amino acid change; no missense residue context is available. Details ▾Hide ▴
Evidence considered
- Synonymous variant (p.Ser547=)
- PM5 candidate harvesting could not identify same-residue comparator variants. PM5 mode='unknown'
- eligible_for_classic_pm5_search=false.
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. NM_000264.5:c.1641C>T is a synonymous variant, not a missense change. Details ▾Hide ▴
Evidence considered
- Synonymous variant (p.Ser547=)
- PP2 criterion is restricted to missense variants.
BP1 N/ABP1 applies to missense variants in genes where only truncating variants cause disease. NM_000264.5:c.1641C>T is a synonymous variant, not a missense change. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- BP1 is restricted to missense variants.
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions. NM_000264.5:c.1641C>T is a single-nucleotide substitution, not an in-frame indel. Details ▾Hide ▴
Evidence considered
- Substitution variant
- BP3 is restricted to in-frame indels.
Identifiers
- Gene
- PTCH1
- Transcript
- NM_000264.5
- Coding (HGVS c.)
- NM_000264.5:c.1641C>T
- Protein (HGVS p.)
- NP_000255.2:p.(Ser547=)
- GRCh38
- chr9:95476121 G>A
- GRCh37
- chr9:98238403 G>A
- ClinVar
- 1785771, 132700
- COSMIC
- COSV59461249
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
18,153 / 1,613,520 alleles
AF 0.0113 · 125 homozygotes · FAF 0.0138
gnomAD v2.1
2,242 / 281,002 alleles
AF 0.00798 · 17 homozygotes · FAF 0.0132
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.011 · 18153 / 1,613,520 alleles · 125 hom · FAF 0.014
| Amish28 / 912 | 0.031 |
| European (non-Finnish)16532 / 1,179,780 | 0.014119 hom |
| European (Finnish)673 / 63,906 | 0.0113 hom |
| Remaining individuals514 / 62,474 | 0.00822 hom |
| Admixed American195 / 59,968 | 0.00331 hom |
| African/African American178 / 75,034 | 0.0024 |
| Ashkenazi Jewish17 / 29,592 | 0.00057 |
| South Asian15 / 90,940 | 0.00016 |
| East Asian1 / 44,856 | 2.2e-05 |
0 alternate alleles recorded in 1 other group: Middle Eastern.
gnomAD v2.1
AF 0.008 · 2242 / 281,002 alleles · 17 hom · FAF 0.013
| European (non-Finnish)1756 / 128,296 | 0.01414 hom |
| European (Finnish)267 / 24,840 | 0.0112 hom |
| Remaining individuals61 / 7,184 | 0.0085 |
| Admixed American90 / 35,306 | 0.00251 hom |
| African/African American59 / 24,772 | 0.0024 |
| Ashkenazi Jewish6 / 10,332 | 0.00058 |
| South Asian3 / 30,404 | 9.9e-05 |
0 alternate alleles recorded in 1 other group: East Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.0112506; MAF= 1.12506%, 18153/1613520 alleles, homozygotes = 125) and has highest observed frequency in the Amish population (AF= 0.0307018; MAF= 3.07018%, 28/912 alleles, homozygotes = 0); grpmax FAF= 0.0138338.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00797859; MAF= 0.79786%, 2242/281002 alleles, homozygotes = 17) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0136871; MAF= 1.36871%, 1756/128296 alleles, homozygotes = 14); grpmax FAF= 0.0131535.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.006785365324069048, 125/18422 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splicing impact (max delta score=0.00 for all acceptor and donor gain/loss predictions). This is a synonymous variant (p.Ser547=) at a position where no splicing disruption is predicted. While REVEL and BayesDel scores are unavailable, the absence of any in silico evidence of deleteriousness supports a benign interpretation. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta=0.00
- no predicted acceptor gain/loss or donor gain/loss. Synonymous substitution with no predicted impact on splicing or protein sequence.
Sources
BP7 SupportingNM_000264.5:c.1641C>T is a synonymous variant (p.Ser547=) at a nucleotide position with no predicted splicing impact. SpliceAI predicts a max delta score of 0.00, indicating the variant does not alter any splice site. In the absence of evidence for an effect on splicing, synonymous variants are generally considered likely benign under BP7. Details ▾Hide ▴
Evidence considered
- Synonymous variant (p.Ser547=)
- SpliceAI max delta=0.00 (no predicted splicing impact). No cryptic splice site creation or loss predicted.
Sources
PP3 Multiple lines of computational evidence do NOT support a deleterious effect. SpliceAI predicts no splicing impact (max delta=0.00). REVEL and BayesDel scores are unavailable. This is a synonymous variant with no in silico evidence of functional disruption. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta score=0.00 (no predicted splicing impact for any acceptor/donor gain or loss). REVEL: not found. BayesDel: not found. No computational tool predicts a deleterious effect for this synonymous variant.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Recorded publications
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PMID 21188540 ↗Heterogeneity of familial medulloblastoma and contribution of germline PTCH1 and SUFU mutations to sporadic medulloblastoma.Slade I et al. · 2011c.1641C>T (rs2066830, p.S547S) identified among 9 synonymous non-pathogenic PTCH1 variants detected during mutational analysis of 78 sporadic medulloblastoma cases. The authors explicitly classified all synonymous variants as non-pathogenic, noting they identified 'six non-synonymous and nine synonymous non-pathogenic PTCH1 variants.'Names this variant
Quoted passage
We did not identify any pathogenic mutations. We identified six non-synonymous and nine synonymous non-pathogenic PTCH1 variants (Table 1).
Results paragraph 2; Table 1 (Exon 12 row)
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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.This is the ACMG/AMP standards and guidelines document for sequence variant interpretation. It describes the framework and criteria but does not discuss any specific PTCH1 variants. NM_000264.5:c.1641C>T was not identified in this paper.Does not name this variant
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.This paper describes the Sherloc variant scoring system used by Quest Diagnostics. It presents aggregate statistics on variant classification across 338 genes but does not discuss individual PTCH1 variants. NM_000264.5:c.1641C>T was not identified in this paper.Does not name this variant
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PMID 29498494 ↗Potential hot spot for de novo mutations in PTCH1 gene in Gorlin syndrome patients: a case report of twins from Croatia.Musani V et al. · 2018c.1641C>T (rs2066830) was typed as part of a 14-polymorphism PTCH1 panel for linkage analysis in twins with Gorlin syndrome caused by a de novo c.3364_3365delAT mutation. All family members (both affected twins and both unaffected parents) were wild-type (WT) for c.1641C>T. The variant was not present in this family, confirming it is not the causative mutation.Names this variant
Quoted passage
c.1641C>T: WT / WT / WT / WT
Table 2 (polymorphism linkage analysis)
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PMID 20301330 ↗Nevoid Basal Cell Carcinoma Syndrome.Adam MP et al. · 1993GeneReviews entry for Nevoid Basal Cell Carcinoma Syndrome (Gorlin syndrome). Provides a comprehensive overview of PTCH1-related disease and genetic counseling considerations but does not list specific benign polymorphisms. NM_000264.5:c.1641C>T was not identified in the abstract or available text.Does not name this variant
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PMID 20301702 ↗Holoprosencephaly Overview.Adam MP et al. · 1993GeneReviews entry for Holoprosencephaly Overview. This chapter discusses holoprosencephaly genetics broadly and is not specific to PTCH1 variants. NM_000264.5:c.1641C>T was not identified in the abstract or available text.Does not name this variant
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PMID 21304560 ↗Clinical utility gene card for: Gorlin syndrome.Lo Muzio L et al. · 2011Clinical utility gene card for Gorlin syndrome providing recommendations for PTCH1 genetic testing. Describes the clinical context for PTCH1 testing but does not enumerate specific benign polymorphisms. NM_000264.5:c.1641C>T was not identified in the abstract or available text.Does not name this variant
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PMID 23313819 ↗PTCH1 gene polymorphisms in ovarian tumors: potential protective role of c.3944T allele.Musani V et al. · 2013c.1641C>T (rs2066830) was detected as a synonymous polymorphism p.(=) during PTCH1 genotyping in ovarian tumor patients and healthy controls. The variant was found in ovarian dermoid samples (MAF 2.6%) and healthy controls (MAF 3.3%), but was absent from ovarian carcinoma and fibroma samples. The authors classified this as a common PTCH1 polymorphism.Names this variant
Quoted passage
polymorphism c.1641C>T was found in dermoids and controls
Results section 3.3; Table 1 (Exon 12, rs2066830 row)
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Sherloc refinement of ACMG-AMP criteria paper describing a comprehensive variant classification framework. Discusses methodology and provides general classification rules but does not discuss specific PTCH1 variants. NM_000264.5:c.1641C>T was not identified in the available text.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
18,153 / 1,613,520 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
14 Benign · 1 Likely benign · 1 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/132700/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-98238403-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-95476121-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-95476121-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000264.5%3Ac.1641…
- OncoKB ↗www.oncokb.org/gene/PTCH1/S547=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=127895136
- 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= 0.0112506; MAF= 1.12506%, 18153/1613520 alleles, homozygotes = 125) and has highest observed frequency in the Amish population (AF= 0.0307018; MAF= 3.07018%, 28/912 alleles, homozygotes = 0); grpmax FAF= 0.0138338.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00797859; MAF= 0.79786%, 2242/281002 alleles, homozygotes = 17) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0136871; MAF= 1.36871%, 1756/128296 alleles, homozygotes = 14); grpmax FAF= 0.0131535.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.006785365324069048, 125/18422 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Benign (14 clinical laboratories) and as Likely benign (1 clinical laboratory) and as benign (1 clinical laboratory). (ClinVarID = 132700)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59461249, n = 5 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.