NM_000264.5:c.4033C>G

PTCH1 · NP_000255.2:p.(Arg1345Gly) · NM_000264.5

GRCh37: chr9:98209505 G>C · GRCh38: chr9:95447223 G>C

Gene: PTCH1 Transcript: NM_000264.5

Final call

VUS

PM2 supporting BP6 supporting

Variant details

Gene

PTCH1

Transcript

NM_000264.5

Protein

NP_000255.2:p.(Arg1345Gly)

gnomAD AF

2.4820362625497957e-06 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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%).

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.

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.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	N/A	This is a missense variant (c.4033C>G, p.Arg1345Gly). PVS1 is reserved for null variants (nonsense, frameshift, canonical splice ±1,2). The variant does not fall into any PVS1 null-variant bucket and SpliceAI predicts no cryptic splice impact (max delta = 0.00).	pvs1_generic_framework spliceai
PS1	Not met	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.	clinvar
PS2	Not met	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	Not met	No published functional studies have tested the specific effect of p.Arg1345Gly on PTCH1 protein function or Hedgehog pathway signaling. Well-established PTCH1 functional assays exist but have not been applied to this variant.
PS4	Not met	No case-control study demonstrates statistically significant enrichment of this variant in PTCH1-associated disease (Gorlin syndrome) cases versus controls. The variant is present at extremely low frequency in gnomAD but without accompanying phenotype-enrichment data.	gnomad_v2 gnomad_v4 clinvar
PS5	Not met	PS5 requires a reputable source to have reported the variant as pathogenic. ClinVar classifications for this variant are Benign (Labcorp Genetics) and Uncertain significance (Ambry Genetics). No reputable source has reported this variant as pathogenic.	clinvar
PM1	Not assessed	p.Arg1345 lies within the C-terminal domain (CTD, residues ~1188-1447) of PTCH1, a region implicated in Hedgehog pathway regulation. However, no formal PM1 mutational hotspot domain has been defined for PTCH1 by a ClinGen CSPEC/VCEP, and benign missense variation within this domain in population databases has not been systematically evaluated to satisfy generic PM1 requirements.
PM2	Met	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 gnomad_v4
PM5	N/A	No same-residue alternate pathogenic missense candidate could be confirmed to satisfy classic PM5 comparator semantics. Automated candidate harvesting returned zero eligible comparators.	pm5_candidates
PM6	Not met	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	Not met	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	Not assessed	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). Without a CSPEC/VCEP framework providing gene-level PP2 qualification or direct gnomAD constraint metrics for PTCH1 in the evidence packet, PP2 cannot be reliably applied in generic ACMG mode.
PP3	Not met	Computational evidence does not support a deleterious effect. The BayesDel score is -0.078 (benign range). REVEL score is not available for this variant. SpliceAI max delta is 0.00 (no splice impact predicted). Multiple lines of in silico evidence do not converge on a damaging prediction.	bayesdel spliceai
PP4	Not met	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	Not met	PP5 requires a reputable source to have recently reported the variant as pathogenic. ClinVar classification for this variant is Benign (Labcorp Genetics) and Uncertain significance (Ambry Genetics). No reputable source reports the variant as pathogenic.	clinvar
BA1	Not met	Allele frequency in gnomAD is well below the BA1 threshold of >1% (non-VCEP generic cutoff). gnomAD v2.1 AF = 0.00081%; gnomAD v4.1 AF = 0.00025%.	gnomad_v2 gnomad_v4
BS1	Not met	Allele frequency in gnomAD is well below the BS1 threshold of >0.3% (non-VCEP generic cutoff). gnomAD v2.1 AF = 0.00081%; gnomAD v4.1 AF = 0.00025%.	gnomad_v2 gnomad_v4
BS2	Not met	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. gnomAD does not provide phenotype data, and the very low allele count precludes confident application of BS2. Gorlin syndrome also has variable expressivity.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies have demonstrated that p.Arg1345Gly does not alter PTCH1 protein function or Hedgehog pathway signaling. No variant-specific functional data are available.
BS4	Not met	No pedigree or family data are available to assess non-segregation of this variant with PTCH1-associated disease. BS4 requires documented lack of segregation in an affected family member.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants cause disease. PTCH1 harbors many established pathogenic missense variants associated with Gorlin syndrome; therefore BP1 is not applicable.
BP2	Not met	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. Given PTCH1 is an autosomal dominant disorder gene, such an observation is rare.
BP4	Not met	Insufficient computational evidence to meet BP4. BayesDel score of -0.078 falls in the benign range, but this represents only one meta-predictor. SpliceAI max delta of 0.00 is neutral. REVEL is unavailable. BP4 requires multiple lines of computational evidence suggesting no impact; a single borderline-benign meta-predictor score does not satisfy this threshold.	bayesdel spliceai
BP5	Not met	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.
BP6	Met	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
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact. This is a missense variant (c.4033C>G, p.Arg1345Gly), not synonymous.

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