NM_000264.5:c.113G>A

PTCH1 · NP_000255.2:p.(Gly38Glu) · NM_000264.5

GRCh37: chr9:98270531 C>T · GRCh38: chr9:95508249 C>T

Gene: PTCH1 Transcript: NM_000264.5

Final call

Likely Benign

BS2 supporting benign BS4 supporting benign BP4 supporting benign BP6 supporting benign

Variant details

Gene

PTCH1

Transcript

NM_000264.5

Protein

NP_000255.2:p.(Gly38Glu)

gnomAD AF

0.0001247646626550669 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000264.5:c.113G>A (p.Gly38Glu) is a missense variant in PTCH1. PVS1 is not applicable as the variant does not fall into a null-variant class.

This variant is present in gnomAD population databases at frequencies (v2.1 AF=0.0096%, 25 alleles; v4.1 AF=0.0125%, 200 alleles) that exceed the maximum credible allele frequency for Gorlin syndrome (prevalence ~1/50,000-1/256,000), arguing against a highly penetrant pathogenic role.

Multiple in silico predictors consistently suggest a benign effect: REVEL score 0.162, BayesDel score -0.434, and SpliceAI max delta 0.02 (BP4).

The variant has been observed in a healthy adult carrier (mother of proband in Taeubner et al. 2018, PMID:29230040) who is heterozygous for PTCH1 p.G38E with no personal or family cancer history across three generations (BS2).

The variant does not segregate with Gorlin syndrome features in the only reported family: the variant-carrying mother is unaffected, and the proband's congenital embryonal rhabdomyosarcoma occurred in the context of a co-occurring PTCH2 variant (BS4).

Multiple clinical laboratories in ClinVar have classified this variant as Likely benign (4 labs) or Benign (1 lab), with only 2 reporting Uncertain significance and none reporting Pathogenic/Likely pathogenic (BP6).

No pathogenic criteria are met. Applying the ACMG/AMP 2015 combination rules: 4 supporting benign criteria (BS2, BS4, BP4, BP6) are fulfilled, which classifies this variant as Likely benign.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	NM_000264.5:c.113G>A is a missense variant (p.Gly38Glu), not a null variant (nonsense, frameshift, or canonical splice site). Per ClinGen SVI PVS1 recommendations (PMC6185798), PVS1 is not applicable to missense variants.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No alternate nucleotide change at the same amino acid position (p.Gly38) has been reported as pathogenic. No data available to support PS1.
PS2	Not met	The variant was inherited from the mother, as confirmed by trio whole-exome sequencing in PMID:29230040. It is not a de novo occurrence.	PMID:29230040
PS3	Not met	No variant-specific functional assay demonstrating a deleterious effect has been performed. The qRT-PCR data from PMID:29230040 measures patient-derived expression levels, not a controlled functional characterization of the variant. In silico predictors (REVEL 0.162, BayesDel -0.434) are in the benign range.	PMID:29230040 revel bayesdel
PS4	Not met	The variant is present in gnomAD population databases at frequencies (v2.1: 0.0096%, v4.1: 0.0125%) that are inconsistent with a highly penetrant pathogenic variant for Gorlin syndrome (prevalence ~1/50,000-1/256,000). No case-control data demonstrating enrichment in affected individuals exists.	gnomad_v2 gnomad_v4
PS5	Not met	No reputable source has recently classified this variant as pathogenic. ClinVar reports Likely benign (4 clinical laboratories), Uncertain significance (2), and Benign (1).	clinvar
PM1	Not met	p.Gly38 is located in the N-terminal extracellular region of PTCH1 (exon 1), N-terminal to the first transmembrane domain and well outside the sterol-sensing domain (SSD). This position is not in a recognized critical functional domain and is not a statistically significant mutational hotspot per cancerhotspots.org.
PM2	Not met	The variant is present in gnomAD population databases at frequencies inconsistent with absence from controls: v2.1 AF=0.0096% (25/259,610 alleles) and v4.1 AF=0.0125% (200/1,603,018 alleles). While technical AF is below the 0.1% PM2 threshold, 200 alleles in gnomAD v4.1 is not compatible with the PM2 concept of absence from population databases for a rare dominant disorder.	gnomad_v2 gnomad_v4
PM5	Not met	No alternative pathogenic missense variant at the same amino acid residue (p.Gly38) was identified in ClinVar. PM5 criteria require a different amino acid change at the same position that is classified as pathogenic.	pm5_candidates
PM6	Not met	The variant is inherited from the mother, not de novo. Trio WES in PMID:29230040 confirmed maternal transmission. PM6 requires a de novo occurrence with both maternity and paternity confirmed.	PMID:29230040
PP1	Not met	The variant does not cosegregate with disease in the only reported family (PMID:29230040). The variant was transmitted from the mother, who has no cancer history, and the family history is unremarkable for three generations.	PMID:29230040
PP2	Not met	No gene-level missense constraint data was available to establish a low rate of benign missense variation in PTCH1. The variant itself is present in gnomAD, suggesting missense variation at this gene is tolerated in the population.
PP3	Not met	Multiple in silico predictors uniformly suggest a benign effect: REVEL score 0.162 (below 0.5 threshold), BayesDel score -0.434 (negative), and SpliceAI max delta 0.02 (no predicted splicing impact). PP3 requires pathogenic in silico predictions.	revel bayesdel spliceai
PP4	Not met	The proband in PMID:29230040 presented with congenital embryonal rhabdomyosarcoma, which can be part of the Gorlin syndrome spectrum. However, the variant-carrying mother is phenotypically unaffected, and the phenotype is not sufficiently specific to support PP4.	PMID:29230040
PP5	Not met	No reputable source has classified this variant as pathogenic. ClinVar reports Likely benign (4 labs), Uncertain significance (2 labs), and Benign (1 lab). PP5 requires a reputable source to have recently reported the variant as pathogenic.	clinvar
BA1	Not met	gnomAD allele frequency (v2.1: 0.0096%, v4.1: 0.0125%) is well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD allele frequency (v2.1: 0.0096%, v4.1: 0.0125%) is below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Met	The variant has been observed in a healthy adult heterozygous carrier: the mother of the proband in PMID:29230040 carries the variant and has no cancer history, with an unremarkable family history spanning three generations. Additionally, the variant is present in gnomAD population databases (200 alleles in v4.1), indicating it is tolerated in the general population.	PMID:29230040 gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional study has demonstrated that p.G38E has no damaging effect on protein function. The available expression data from patient samples (PMID:29230040) is not a controlled functional assay, and in silico benign predictions alone are insufficient for BS3.	PMID:29230040 revel bayesdel
BS4	Met	The variant does not segregate with disease in the only reported family (PMID:29230040). The variant was inherited from the mother, who has no personal or family history of Gorlin syndrome-associated features across three generations, while the proband presented with congenital embryonal rhabdomyosarcoma. This lack of segregation supports a benign interpretation.	PMID:29230040
BP1	Not met	PTCH1 is a gene in which both missense and truncating variants are established mechanisms of disease for Gorlin syndrome. BP1 applies only when primarily truncating variants cause disease.
BP2	Not met	No evidence that this variant has been observed in trans with a known pathogenic PTCH1 variant. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP4	Met	Multiple lines of computational evidence suggest no impact on gene product: REVEL score 0.162 (benign range, below 0.5 threshold), BayesDel score -0.434 (negative, predicting benign), and SpliceAI max delta score 0.02 (no predicted splicing impact).	revel bayesdel spliceai
BP5	Not met	The proband in PMID:29230040 also harbored a PTCH2 p.His622Tyr variant, but this was described as a co-occurring/modifier variant, not an alternate molecular basis for the phenotype. BP5 requires a clearly established alternate cause.	PMID:29230040
BP6	Met	Multiple clinical laboratories have classified this variant as Likely benign or Benign in ClinVar (variation ID 216367): 4 labs report Likely benign, 1 reports Benign. Only 2 report Uncertain significance. No submitter reports Pathogenic or Likely pathogenic.	clinvar
BP7	N/A	NM_000264.5:c.113G>A is a missense variant (p.Gly38Glu), not a synonymous (silent) variant. BP7 is only applicable to synonymous variants with no predicted splice impact.

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