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PTCH2 – Nevoid Basal Cell Carcinoma Syndrome

Nevoid Basal Cell Carcinoma Syndrome (NBCCS) is an autosomal dominant tumor predisposition syndrome most often caused by heterozygous PTCH1 mutations. A single case report described a 13-year-old girl with multiple keratocystic odontogenic tumors and rib anomalies carrying a heterozygous PTCH2 frameshift variant, c.1172_1173del (p.Phe390_Ser391insTer), supporting a potential causative role for PTCH2 in NBCCS despite milder phenotypic presentation (PMID:23479190). However, no additional affected relatives were reported, and a healthy individual homozygous for a PTCH2 frameshift (c.269del (p.Gly90AlafsTer4)) and her heterozygous daughter show no NBCCS features, calling into question pathogenicity of PTCH2 loss-of-function alleles (PMID:30820324).

Functional assays have demonstrated that a PTCH2 missense variant, c.2156G>A (p.Arg719Gln), abolishes PTCH2 inhibitory activity on Hedgehog signaling in cell‐based reporter assays (PMID:18285427), and distinct PTCH2 splice isoforms modulate SHH‐N internalization without fully recapitulating PTCH1 function (PMID:14613484). However, a cohort of 21 PTCH1/SUFU-negative GS families yielded no pathogenic PTCH2 variants, and population data reveal homozygous PTCH2 loss-of-function alleles in healthy individuals, refuting a major role for PTCH2 in NBCCS predisposition (PMID:34170463).

Key Take-home: Current genetic and population evidence refute PTCH2 as a primary NBCCS gene; PTCH2 should be excluded from clinical diagnostic panels for Gorlin syndrome.

References

  • Familial cancer • 2013 • Frameshift mutation in the PTCH2 gene can cause nevoid basal cell carcinoma syndrome. PMID:23479190
  • Human genome variation • 2019 • A healthy individual with a homozygous PTCH2 frameshift variant: Are variants of PTCH2 associated with nevoid basal cell carcinoma syndrome? PMID:30820324
  • Familial cancer • 2022 • PTCH2 is not a strong candidate gene for gorlin syndrome predisposition. PMID:34170463
  • Journal of medical genetics • 2008 • A missense mutation in PTCH2 underlies dominantly inherited NBCCS in a Chinese family. PMID:18285427
  • The Biochemical journal • 2004 • Distinct roles of PTCH2 splice variants in Hedgehog signalling. PMID:14613484

Evidence Based Scoring (AI generated)

Gene–Disease Association

Refuted

No pathogenic PTCH2 variants identified in 21 PTCH1/SUFU-negative GS families and presence of healthy homozygous LoF individual; conflicting case reports ([PMID:34170463]; [PMID:30820324])

Genetic Evidence

Limited

Single proband with PTCH2 frameshift reported without segregation; healthy homozygotes and absence in cohort studies ([PMID:23479190]; [PMID:30820324]; [PMID:34170463])

Functional Evidence

Limited

In vitro loss of PTCH2 inhibitory activity for p.Arg719Gln and differential HH pathway regulation by splice isoforms ([PMID:18285427]; [PMID:14613484])