NM_000264.5:c.2438C>T

PTCH1 · NP_000255.2:p.(Pro813Leu) · NM_000264.5

GRCh37: chr9:98229520 G>A · GRCh38: chr9:95467238 G>A

Gene: PTCH1 Transcript: NM_000264.5

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

PTCH1

Transcript

NM_000264.5

Protein

NP_000255.2:p.(Pro813Leu)

gnomAD AF

2.4807278455498844e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000264.5:c.2438C>T (p.Pro813Leu) is a missense variant in exon 15 of PTCH1, a gene in which loss-of-function variants are an established cause of Gorlin syndrome (nevoid basal cell carcinoma syndrome).

This variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (4/1,612,430 alleles, AF=2.48e-6, 0 homozygotes), meeting PM2 at moderate strength.

Multiple lines of computational evidence suggest no significant impact on the gene product: BayesDel score is 0.0037 (strongly predicts benign) and SpliceAI max delta is 0.01 (no splicing impact), meeting BP4 at supporting benign level.

The variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp/Invitae, SCV005813886). It has been observed somatically in COSMIC (COSV59468245, n=2) but this does not inform germline pathogenicity.

No variant-specific functional studies, segregation data, case-control analyses, or de novo observations were identified. Five literature-triage papers (PMIDs 15604628, 20301330, 21304560, 26389210, 26389333) were reviewed; none mention NM_000264.5:c.2438C>T.

Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4) are present. These do not meet the threshold for Likely Pathogenic, Likely Benign, Pathogenic, or Benign. The variant is classified as a Variant of Uncertain Significance.

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.2438C>T, p.Pro813Leu) in exon 15 of PTCH1. It does not fall into the generic PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). The pvs1_variant_assessment confirms bucket='other' and apply_generic_pvs1_framework=false.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No known pathogenic missense variant at Pro813 arising from a different nucleotide change has been identified. The same-residue PM5 candidate search returned zero comparator variants, and no reputable source has established P813L as pathogenic via any other nucleotide substitution.	pm5_candidates
PS2	Not met	No de novo observation with confirmed maternity and paternity has been reported for this variant in any available source.
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrate a damaging effect for NM_000264.5:c.2438C>T (p.Pro813Leu). OncoKB reports no variant-specific reviewed functional evidence. COSMIC reports n=2 somatic observations (COSV59468245), but somatic occurrence alone does not constitute functional evidence of germline pathogenicity.	oncokb
PS4	Not met	The prevalence of this variant in affected individuals has not been shown to be significantly increased compared to controls. A single clinical laboratory submission in ClinVar (Labcorp/Invitae) classifies it as VUS without reporting patient counts or case-control statistics. The variant is present in gnomAD v4.1 at AF=2.48e-6 (4 alleles), which does not independently establish enriched prevalence in affected populations.	clinvar gnomad_v4
PS5	Not met	No reputable source has classified this variant as pathogenic. The sole ClinVar submission (Labcorp/Invitae, SCV005813886) classifies it as Uncertain significance.	clinvar
PM1	Not met	Residue Pro813 does not lie within a statistically significant mutational hotspot as determined by cancerhotspots.org. No evidence was identified that this residue resides in a well-characterized critical functional domain without benign variation. PTCH1 is a large multi-pass transmembrane protein; domain-level PM1 evidence was not established for this residue.
PM2	Met	This variant is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1 (4/1,612,430 alleles; AF=2.48e-6; 0 homozygotes; grpmax FAF=7.9e-7). The allele frequency of 0.00025% is well below the 0.1% PM2 threshold for non-VCEP frameworks. The submitting laboratory (Labcorp/Invitae) also applied PM2 for this variant.	gnomad_v2 gnomad_v4 gnomad_canada clinvar
PM5	N/A	No same-residue pathogenic missense comparator variant at Pro813 was identified by the automated PM5 candidate search. The pm5_candidates search returned zero candidates. Without a confirmed pathogenic missense at Pro813 as comparator, PM5 cannot be applied.	pm5_candidates
PM6	Not met	No de novo observation (without confirmed parentage) has been reported for this variant in ClinVar, the reviewed literature, or any other source.
PP1	Not met	No co-segregation data are available for this variant. No family studies were identified in the reviewed literature.
PP2	Not met	While PTCH1 loss-of-function is an established disease mechanism for Gorlin syndrome, missense variants are also well-documented as causative in this disorder. Insufficient evidence that PTCH1 meets the PP2 threshold of a gene with a low rate of benign missense variation where missense is a common disease mechanism. No HCI prior or custom PP2 score was available.
PP3	Not met	In silico predictions are conflicting and do not provide multiple lines of computational support for a deleterious effect. REVEL score is 0.656 (borderline, below the >0.75 threshold for strong evidence). BayesDel score is 0.0037, which strongly predicts a benign effect. SpliceAI max delta is 0.01, indicating no predicted splicing impact. The preponderance of computational evidence does not support a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No proband phenotype information is available. The variant's specificity for Gorlin syndrome / nevoid basal cell carcinoma syndrome cannot be assessed without clinical data.
PP5	Not met	No reputable source has classified this variant as pathogenic. The single ClinVar submission classifies it as Uncertain significance. Although five papers (PMIDs 15604628, 20301330, 21304560, 26389210, 26389333) were flagged by literature triage as candidate PP5/PS4 sources, none mention the specific variant NM_000264.5:c.2438C>T. They are gene-level or general guideline publications.	clinvar
BA1	Not met	The allele frequency in gnomAD v4.1 is 2.48e-6 (0.00025%), far below the 1% BA1 threshold for non-VCEP frameworks. The variant is absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The allele frequency in gnomAD v4.1 is 0.00025%, below the 0.3% BS1 threshold for non-VCEP frameworks.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	This variant has not been observed in the homozygous state (0 homozygotes in gnomAD v4.1, 0 in v2.1) and no control population data demonstrate observation in healthy adults at a frequency that would meet BS2.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate no damaging effect for this variant. While BayesDel predicts a benign score (0.0037), computational prediction alone does not meet the BS3 threshold, which requires experimental functional evidence showing no deleterious effect.	bayesdel
BS4	Not met	No segregation data are available for this variant. Lack of segregation in affected family members cannot be assessed.
BP1	Not met	Although PTCH1 loss-of-function is an established disease mechanism for Gorlin syndrome, missense variants in PTCH1 are also well-documented as causative. The gene is not characterized by a disease mechanism that is primarily truncating to the exclusion of missense changes.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a known pathogenic PTCH1 variant has been reported. No data are available to assess BP2.
BP4	Met	Multiple lines of computational evidence suggest this variant does not have a significant impact on the gene product. BayesDel score is 0.0037, which strongly predicts a benign effect. SpliceAI max delta is 0.01, indicating no predicted splicing alteration. The REVEL score of 0.656 is borderline and does not outweigh the preponderance of benign computational evidence.	revel bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternative molecular basis for disease has been reported.
BP6	Not met	No reputable source has classified this variant as benign. The sole ClinVar classification is Uncertain significance.	clinvar
BP7	N/A	This is a missense variant (c.2438C>T, p.Pro813Leu), not a synonymous or intronic variant. BP7 is restricted to synonymous variants with no predicted splicing impact.
BP3	N/A	Skipped: this is a substitution variant, not an in-frame indel.
PM3	N/A	Skipped: PTCH1-associated Gorlin syndrome is autosomal dominant; PM3 (in trans with pathogenic variant) is designed for recessive disorders.
PM4	N/A	Skipped: this is a substitution variant, not an in-frame deletion/insertion or stop-loss.

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