LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-01
Case ID: NM_000264.5_c.1913G_A_20260801_073434
Framework: ACMG/AMP 2015
Variant classification summary

NM_000264.5:c.1913G>A

PTCH1  · NP_000255.2:p.(Arg638His)  · NM_000264.5
GRCh37: chr9:98231370 C>T  ·  GRCh38: chr9:95469088 C>T
Gene: PTCH1 Transcript: NM_000264.5
Final call
Likely Benign
PM2 supporting BS2 supporting benign BP4 supporting benign BP6 supporting benign
All criteria require review: For research and educational purposes only.
Variant details
Gene
PTCH1
Transcript
NM_000264.5
Protein
NP_000255.2:p.(Arg638His)
gnomAD AF
7.807310616951034e-05 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
This variant is a missense change (p.Arg638His) in PTCH1, a gene in which loss-of-function is an established mechanism for Gorlin syndrome (nevoid basal cell carcinoma syndrome), an autosomal dominant disorder with high penetrance and early onset.
2
The variant is present in gnomAD population databases at low frequency overall (v2.1: 33/282,644 alleles, AF=0.012%; v4.1: 126/1,613,872 alleles, AF=0.008%), with the highest subpopulation frequency in Africans/African Americans (0.112% in v2.1). No homozygotes have been observed.
3
The variant meets PM2 at supporting level: overall allele frequency is below the 0.1% threshold, though the African subpopulation frequency is borderline (0.112% in v2.1).
4
Five of six clinical diagnostic laboratories in ClinVar classify this variant as Likely benign or Benign (ClinVar ID 220182), providing supporting evidence for a benign interpretation (BP6_supporting).
5
Multiple in silico predictors support a benign effect: REVEL score 0.378, BayesDel score -0.243824, and SpliceAI predicts no splicing impact (max delta 0.05). These provide supporting benign evidence (BP4_supporting).
6
The variant has been observed in multiple individuals in gnomAD presumed to be healthy adults, which is inconsistent with a fully penetrant early-onset dominant disorder such as Gorlin syndrome, providing additional supporting benign evidence (BS2_supporting).
7
No pathogenic evidence criteria were met: there is no functional data supporting a damaging effect (PS3 not met), no case-control enrichment (PS4 not met), no de novo reports (PS2/PM6 not met), no segregation data (PP1 not met), the variant is not in a known hotspot or critical domain (PM1 not met), and no reputable source reports it as pathogenic (PP5 not met).
8
No functional studies of p.Arg638His or a systematically characterized range including this residue were identified. The variant has not been experimentally characterized for its effect on Hedgehog signaling, PTCH1-SMO interaction, or protein trafficking.
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 N/A NM_000264.5:c.1913G>A is a missense variant (p.Arg638His) and does not fall into generic PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). The PVS1 generic framework was not applied.
pvs1_variant_assessment pvs1_generic_framework
PS1 Not met No evidence identified of a different nucleotide change at c.1913 producing the same p.Arg638His amino acid substitution that has been independently classified as pathogenic.
PS2 Not met No de novo occurrence of this variant has been reported with confirmed maternity and paternity testing.
PS3 Not met No functional data were identified for NM_000264.5:c.1913G>A (p.Arg638His) or for a systematically characterized range that includes this residue. REVEL score 0.378 and BayesDel score -0.243824 do not independently meet PS3 criteria. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional evidence.
revel bayesdel oncokb
PS4 Not met No case-control data demonstrate enrichment of this variant in affected individuals compared to population controls. The variant is observed in gnomAD population databases at low frequency.
gnomad_v2 gnomad_v4
PS5 Not met No de novo occurrence of this variant has been reported in the literature or ClinVar submissions, with or without confirmed maternity and paternity.
PM1 Not met Residue Arg638 does not lie within a statistically significant missense mutation hotspot (cancerhotspots.org). No CSPEC/VCEP-defined critical functional domain mapping assigns this residue to a domain with sufficient specificity to independently satisfy PM1 under generic ACMG/AMP.
PM2 Met This variant is present in gnomAD at very low frequency overall (v2.1: 33/282,644 alleles, AF=0.012%; v4.1: 126/1,613,872 alleles, AF=0.008%), below the 0.1% threshold for PM2. No homozygotes are observed. The African/African American subpopulation AF is 0.112% in v2.1 (borderline above 0.1%) but 0.087% in v4.1, supporting overall rarity.
gnomad_v2 gnomad_v4
PM5 N/A No pathogenic missense variant at the same amino acid residue (Arg638) was identified in ClinVar. Automated PM5 candidate harvesting returned zero same-residue comparators; classic PM5 semantics could not be confirmed.
pm5_candidates
PM6 Not met No de novo observation of this variant has been reported without confirmed maternity and paternity.
PP1 Not met No cosegregation data are available for this variant; no family studies have been reported.
PP2 Not met PTCH1 disease mechanism is primarily loss-of-function, with truncating variants representing the predominant pathogenic variant class. While missense variants in specific functional domains can be pathogenic, the gene has not been established as having a low rate of benign missense variation where missense is the common disease mechanism — prerequisites for PP2.
pvs1_gene_context
PP3 Not met Multiple in silico predictors do not support a damaging effect: REVEL score 0.378 (below commonly used 0.5 pathogenic threshold), BayesDel score -0.243824 (predicting benign), and SpliceAI max delta 0.05 (no predicted splicing impact). No computational evidence supports pathogenicity.
revel bayesdel spliceai
PP4 Not assessed No patient phenotype or clinical history was provided for this assessment. PP4 requires evaluation of whether the patient's phenotype or family history is specific for PTCH1-associated disease (Gorlin syndrome / NBCCS).
PP5 Not met ClinVar classification for this variant is Likely benign (4 clinical laboratories) and Benign (1 clinical laboratory), with one VUS. No reputable source reports this variant as pathogenic. The ClinVar review status is 'criteria provided, single submitter' (1-star), below the 3-star expert panel threshold required for PP5 application.
clinvar
BA1 Not met Allele frequency in gnomAD (v2.1: 0.012%; v4.1: 0.008%) is far below the 1% threshold for BA1. This variant is rare, not common.
gnomad_v2 gnomad_v4
BS1 Not met The maximum subpopulation allele frequency in gnomAD (African/African American: 0.112% in v2.1, 0.087% in v4.1) is below the 0.3% threshold for BS1. The variant is not observed at a frequency greater than expected for Gorlin syndrome under generic ACMG/AMP criteria.
gnomad_v2 gnomad_v4
BS2 Met This variant has been observed in multiple individuals within gnomAD population databases (33 alleles in v2.1, 126 alleles in v4.1) who are presumed healthy adults based on gnomAD's exclusion of severe pediatric disease. Gorlin syndrome is a highly penetrant autosomal dominant disorder with early onset; observation of this variant in population controls at this frequency is consistent with a benign or low-penetrance variant.
gnomad_v2 gnomad_v4
BS3 Not met No functional studies demonstrating a neutral or benign effect for this variant have been identified. In silico predictions (REVEL 0.378, BayesDel -0.243824) are consistent with a benign effect but do not independently satisfy BS3 criteria, which requires experimental functional evidence.
revel bayesdel oncokb
BS4 Not assessed No family-based segregation data are available to evaluate lack of segregation with disease. BS4 requires observation that the variant does not segregate with disease in affected family members.
BP1 Not met PTCH1 disease mechanism includes both truncating and missense variants. While loss-of-function through truncation is the predominant mechanism, pathogenic missense variants in key functional domains (e.g., sterol-sensing domain, extracellular loops) are well established in Gorlin syndrome. BP1 requires that primarily truncating variants cause disease, which is not clearly satisfied for PTCH1.
pvs1_gene_context
BP2 Not met No evidence that this variant has been observed in trans with a known pathogenic PTCH1 variant, or in cis with a pathogenic variant in any inheritance pattern.
BP3 N/A Variant is a missense substitution, not an in-frame insertion or deletion.
BP4 Met Multiple in silico predictors support a benign effect for this variant: REVEL score 0.378 (below the 0.5 pathogenic threshold), BayesDel score -0.243824 (predicting benign), and SpliceAI max delta 0.05 (no predicted splicing impact). These represent multiple independent lines of computational evidence suggesting no functional consequence.
revel bayesdel spliceai
BP5 Not met No case has been identified in which this variant is observed in an individual with an alternate molecular explanation for the phenotype. BP5 requires a specific case with an alternate molecular basis for disease.
BP6 Met Five clinical diagnostic laboratories classify this variant as Likely benign (4 labs: GeneDx, Ambry Genetics, Eurofins Ntd, Sema4) or Benign (1 lab: Labcorp Genetics/Invitae) in ClinVar (ClinVar ID 220182). One additional laboratory (ARUP) classifies as VUS. While the review status is 'criteria provided, single submitter' (1-star, below the 3-star expert panel threshold), the consensus across multiple independent clinical laboratories reporting with criteria supports BP6 at supporting benign level.
clinvar
BP7 N/A Variant is a missense substitution (c.1913G>A, p.Arg638His), not a synonymous/silent variant. BP7 is reserved for synonymous variants at non-conserved positions without splicing impact.
spliceai
PM3 N/A PTCH1-associated disorders (Gorlin syndrome / NBCCS) are autosomal dominant; PM3 applies to recessive disorders requiring a pathogenic variant in trans.
PM4 N/A Variant is a single nucleotide missense substitution and does not alter protein length via stop-loss, in-frame deletion/insertion, or initiation codon change.
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