NM_000264.5:c.4033C>G (p.Arg1345Gly) is a missense variant in PTCH1, a gene in which loss-of-function variants cause Gorlin syndrome (nevoid basal cell carcinoma syndrome) via an autosomal dominant haploinsufficiency mechanism. This variant is present at extremely low frequency in gnomAD v2.1 (AF=0.00081%, 2/246054 alleles) and gnomAD v4.1 (AF=0.00025%, 4/1611580 alleles), meeting PM2_Supporting (ClinGen SVI threshold ≤0.002%).1 Computational predictors are uninformative or weakly benign: BayesDel score is -0.078 (benign range), SpliceAI delta is 0.00, and REVEL is not available. This does not meet thresholds for PP3 or BP4.2 In ClinVar, Labcorp Genetics (formerly Invitae) has classified this variant as Benign (SCV001497416, criteria provided), while Ambry Genetics has classified it as Uncertain significance (SCV002619761). The Benign classification from a reputable clinical laboratory supports BP6_Supporting.3 No functional studies, segregation data, de novo reports, case-control data, or variant-specific publications were identified for this variant. PVS1, PS1-PS5, PM1, PM5, PM6, PP1-PP5, and the benign criteria BA1, BS1-BS4, BP1-BP2, BP4-BP5, BP7 are either not met or not applicable. The evidence profile yields one supporting pathogenic criterion (PM2_Supporting) and one supporting benign criterion (BP6_Supporting). Per generic ACMG/AMP 2015 combination rules (PMID:25741868), conflicting evidence with equal weight on both sides results in a classification of Variant of Uncertain Significance (VUS).4
PTCH1
Final classification
VUS
PTCH1 c.4033C>G · p.Arg1345Gly
PTCH1
NM_000264.5:c.4033C>G (p.Arg1345Gly) is a missense variant in PTCH1, a gene in which loss-of-function variants cause Gorlin syndrome (nevoid basal cell carcinoma syndrome) via an autosomal dominant haploinsufficiency mechanism.
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, BP6 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP6
VUS
PTCH1 c.4033C>G
PM2 + BP6
→
VUS
Gene diagram
· NM_000264.5 · variants mapped to exon structure
PTCH1
NM_000264.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF = 0.00081% (2/246054 alleles, no homozygotes), gnomAD v4.1 AF = 0.00025% (4/1611580 alleles, no homozygotes). Both allele frequencies are below the ClinGen SVI PM2_Supporting threshold of ≤0.002%. Absent from gnomAD-Canada v1.0.
gnomAD v2.1: 2/246054 allelesAF=8.13e-6grpmax FAF=1.08e-5.
✓
BP6
supporting
Benign
ClinVar contains a Benign classification from Labcorp Genetics (formerly Invitae), a reputable clinical diagnostic laboratory, submitted with criteria provided (SCV001497416; review status: criteria provided, single submitter). A second submitter (Ambry Genetics) classifies the variant as Uncertain significance. While not unanimous, the Benign classification from a major clinical laboratory supports a benign interpretation.
ClinVar: Benign classification by Labcorp Genetics (SCV001497416)criteria provided.ClinVar: Uncertain significance by Ambry Genetics (SCV002619761).
Assessed · not applied
Pathogenic
PS1
No alternative nucleotide change at c.4033 producing the same p.Arg1345Gly amino acid change has been identified as a previously established pathogenic variant in ClinVar or the literature.
PS2
No de novo occurrence of NM_000264.5:c.4033C>G with confirmed paternity and maternity has been identified in public databases (Denovo-db, DECIPHER) or published literature.
PS3
No published functional studies have tested the specific effect of p.Arg1345Gly on PTCH1 protein function or Hedgehog pathway signaling.
PS4
No case-control study demonstrates statistically significant enrichment of this variant in PTCH1-associated disease (Gorlin syndrome) cases versus controls.
PM1
p.Arg1345 lies within the C-terminal domain (CTD, residues ~1188-1447) of PTCH1, a region implicated in Hedgehog pathway regulation.
PM6
No report of this variant as a suspected de novo occurrence without confirmation of paternity and maternity has been identified in public databases or published literature.
PP1
No published cosegregation data exist for NM_000264.5:c.4033C>G with Gorlin syndrome or any other PTCH1-associated phenotype in multiple affected family members.
PP2
PTCH1 missense variants are a known mechanism of disease in Gorlin syndrome, but PP2 requires a demonstrably low rate of benign missense variation (e.g., high gnomAD missense Z-score).
PP3
Computational evidence does not support a deleterious effect.
PP4
No proband phenotype or family history information is available in the case materials to assess whether the presentation is highly specific for PTCH1-associated Gorlin syndrome.
PP5
PP5 requires a reputable source to have recently reported the variant as pathogenic.
Benign
BA1
Allele frequency in gnomAD is well below the BA1 threshold of >1% (non-VCEP generic cutoff).
BS1
Allele frequency in gnomAD is well below the BS1 threshold of >0.3% (non-VCEP generic cutoff).
BS2
Although the variant is observed in gnomAD (2-4 alleles), BS2 requires observation in a healthy adult individual for a fully penetrant dominant disorder with confirmed unaffected status.
BS3
No well-established functional studies have demonstrated that p.Arg1345Gly does not alter PTCH1 protein function or Hedgehog pathway signaling.
BS4
No pedigree or family data are available to assess non-segregation of this variant with PTCH1-associated disease.
BP2
No observation of this variant occurring in trans with a clearly pathogenic PTCH1 variant in a patient without a more severe phenotype has been reported.
BP4
Insufficient computational evidence to meet BP4.
BP5
No case has been reported where this variant is found in a patient with an alternate molecular basis for disease, which would suggest the variant is incidental.
N/A · 4
PVS1 · PM5 · BP1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.48204e-06; MAF= 0.00025%, 4/1611580 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 4.39223e-05; MAF= 0.00439%, 4/91070 alleles, homozygotes = 0); grpmax FAF= 1.425e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 8.1283e-06; MAF= 0.00081%, 2/246054 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.54279e-05; MAF= 0.00654%, 2/30568 alleles, homozygotes = 0); grpmax FAF= 1.083e-05.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00025%
· 4 / 1,611,580
0 hom · FAF 0.0014%
0 hom · FAF 0.0014%
South Asian 4 / 91,070 |
0.0044% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.00081%
· 2 / 246,054
0 hom · FAF 0.0011%
0 hom · FAF 0.0011%
South Asian 2 / 30,568 |
0.0065% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 1010368)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = -0.0783339.
Functional
Unknown Oncogenic Effect
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.
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; COSV59465944, n = 3 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & References.
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
Found
Structured finding pending for this record — see source link.
Applied to
→BP6 supports · met
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
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.
CLINVAR
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR