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).1 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.2 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).3 ClinVar classifies this variant as Benign based on submissions from 14 clinical laboratories; this represents a reputable source reporting a benign classification (BP6).4 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.5 Computational evidence (SpliceAI) predicts no splicing impact; combined with its synonymous nature, this supports a benign interpretation (BP4, BP7).6 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.7
PTCH1
Final classification
Benign
BA1BS1BS2BP4BP6BP7
PTCH1
c.1641C>T
p.Ser547=
This variant
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).
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.
Classification rationale
BA1BS1BS2BP4BP6BP7
Benign
PTCH1 c.1641C>T
BA1 + BS1 + BS2 + BP4 + BP6 + BP7
→
Benign
7
gnomad_v2 ↗gnomad_v4 ↗generic_acmg_combination_rules
Gene diagram
· NM_000264.5 · variants mapped to exon structure
PTCH1
NM_000264.5
Fetching transcript structure from UCSC…
Applied criteria · 6 applied · 14 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 6
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
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).
gnomAD v4.1: total AF=1.125%grpmax FAF=1.38%gnomAD v2.1: NFE subpopulation AF=1.37%
✓
BS1
strong
Benign
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.
gnomAD v2.1: total AF=0.798%gnomAD v4.1: total AF=1.125%. Both far exceed the 0.3% BS1 threshold.
✓
BS2
strong
Benign
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.
gnomAD v2.1: 17 homozygotesgnomAD v4.1: 125 homozygotes. Homozygous state incompatible with a fully penetrant dominant disorder.
✓
BP4
supporting
Benign
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.
SpliceAI: max delta=0.00no predicted acceptor gain/loss or donor gain/loss. Synonymous substitution with no predicted impact on splicing or protein sequence.
✓
BP6
supporting
Benign
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.
ClinVar Variation ID 132700: Benign (14 clinical laboratories)Likely benign (1)benign (1). Overall classification: Benign. Review status: criteria provided
✓
BP7
supporting
Benign
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.
Synonymous variant (p.Ser547=)SpliceAI max delta=0.00 (no predicted splicing impact). No cryptic splice site creation or loss predicted.
Assessed · not applied
· 5 not met · 9 not assessed
Pathogenic
PS2
No de novo observation (with confirmed paternity and maternity) has been reported for NM_000264.5:c.1641C>T in the reviewed literature.
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.
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.
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.
PM2
PM2 requires absence from population controls (or AF <0.1% in non-VCEP framework).
PM6
No de novo observation (without confirmation of paternity and maternity) has been reported for NM_000264.5:c.1641C>T.
PP1
No co-segregation data for NM_000264.5:c.1641C>T with disease in affected families was identified in the reviewed literature.
PP3
Multiple lines of computational evidence do NOT support a deleterious effect.
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.
PP5
Reputable sources do not report NM_000264.5:c.1641C>T as pathogenic.
Benign
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.
BS4
No family-based lack of segregation data were identified for NM_000264.5:c.1641C>T.
BP2
No data were identified showing NM_000264.5:c.1641C>T observed in trans with a known pathogenic PTCH1 variant.
BP5
No case with an alternate molecular basis for disease was identified that harbors NM_000264.5:c.1641C>T.
N/A · 6
PVS1 · PS1 · PM5 · PP2 · BP1 · BP3
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
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.
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.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.006785365324069048, 125/18422 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
1.1%
· 18153 / 1,613,520
125 hom · FAF 1.4%
125 hom · FAF 1.4%
Amish 28 / 912 |
3.1% |
European (non-Finnish) 16532 / 1,179,780 |
1.4% 119 hom |
European (Finnish) 673 / 63,906 |
1.1% 3 hom |
Remaining individuals 514 / 62,474 |
0.82% 2 hom |
Admixed American 195 / 59,968 |
0.33% 1 hom |
African/African American 178 / 75,034 |
0.24% |
Ashkenazi Jewish 17 / 29,592 |
0.057% |
South Asian 15 / 90,940 |
0.016% |
East Asian 1 / 44,856 |
0.0022% |
+ 1 not observed (Middle Eastern)
gnomAD v2.1
0.8%
· 2242 / 281,002
17 hom · FAF 1.3%
17 hom · FAF 1.3%
European (non-Finnish) 1756 / 128,296 |
1.4% 14 hom |
European (Finnish) 267 / 24,840 |
1.1% 2 hom |
Remaining individuals 61 / 7,184 |
0.85% |
Admixed American 90 / 35,306 |
0.25% 1 hom |
African/African American 59 / 24,772 |
0.24% |
Ashkenazi Jewish 6 / 10,332 |
0.058% |
South Asian 3 / 30,404 |
0.0099% |
+ 1 not observed (East Asian)
gnomAD Canada 🇨🇦
0.68%
· 125 / 18,422
0 hom · FAF 0.83%
0 hom · FAF 0.83%
European (non-Finnish) 115 / 11,742 |
0.98% |
Remaining individuals 6 / 1,138 |
0.53% |
Latino/Admixed American 2 / 838 |
0.24% |
Ashkenazi Jewish 1 / 832 |
0.12% |
African/African American 1 / 1,020 |
0.098% |
+ 4 not observed (East Asian, European (Finnish), Middle Eastern, South Asian)
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
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59461249, n = 5 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
21188540 ↗
Heterogeneity of familial medulloblastoma and contribution of germline PTCH1 and SUFU mutations to sporadic medulloblastoma.
CLINVAR
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.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
29498494 ↗
Potential hot spot for de novo mutations in PTCH1 gene in Gorlin syndrome patients: a case report of twins from Croatia.
CLINVAR
23313819 ↗
PTCH1 gene polymorphisms in ovarian tumors: potential protective role of c.3944T allele.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR