NM_000264.5:c.1085C>T

PTCH1 · NP_000255.2:p.(Thr362Ile) · NM_000264.5

GRCh37: chr9:98241412 G>A · GRCh38: chr9:95479130 G>A

Gene: PTCH1 Transcript: NM_000264.5

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

PTCH1

Transcript

NM_000264.5

Protein

NP_000255.2:p.(Thr362Ile)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000264.5:c.1085C>T (p.Thr362Ile) is a missense variant in PTCH1, a gene in which heterozygous pathogenic variants cause Gorlin syndrome (nevoid basal cell carcinoma syndrome), an autosomal dominant tumor-predisposition disorder.

The variant is absent from all population databases queried: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency 0.0% in all populations). This absence meets PM2 at supporting level.

REVEL in silico meta-predictor scores the variant as 0.809, predicting a damaging effect on protein function. BayesDel scores 0.454 (borderline). SpliceAI predicts no significant splicing impact (max delta = 0.11). These computational predictions meet PP3 at supporting level.

The variant has been observed once in somatic cancers (COSMIC COSV59504254) but has not been reported in ClinVar as a germline variant, and no functional studies, de novo reports, segregation data, or case-control studies for this variant were identified in the literature.

No other ACMG/AMP criteria are met. PVS1 is not applicable because this is a missense variant and SpliceAI does not predict a null effect. PS1-PS5, PM1, PM5, PM6, PP1-PP2, PP4-PP5, BA1, BS1-BS4, BP1-BP7 are either not met or not applicable.

Applying the generic ACMG/AMP 2015 final combination rules (Richards et al. 2015, PMID:25741868), two supporting-level pathogenic criteria (PM2_Supporting, PP3_Supporting) are insufficient to reach Likely Pathogenic classification. The variant is classified as a 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	NM_000264.5:c.1085C>T is a missense variant (p.Thr362Ile) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. SpliceAI max delta score is 0.11, indicating no predicted splice impact. PVS1 cannot be applied to this variant class.	spliceai pvs1_generic_framework
PS1	Not met	No established pathogenic variant at the same amino acid residue (Thr362) has been identified in ClinVar or the literature to support PS1. This variant is absent from ClinVar entirely.	clinvar
PS2	Not met	No published reports of de novo occurrence of NM_000264.5:c.1085C>T with confirmed paternity and maternity were identified in the literature or exploratory evidence search.
PS3	Not met	No well-established functional studies demonstrating a damaging effect of p.Thr362Ile on PTCH1 protein function have been identified. OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence.	oncokb
PS4	Not met	No controlled case-control data or proband counts are available to demonstrate that the prevalence of this variant in affected individuals is significantly increased compared to controls. The variant is absent from ClinVar with zero submitters.	clinvar gnomad_v2 gnomad_v4 gnomad_canada
PS5	Not met	No reputable source has recently reported NM_000264.5:c.1085C>T as pathogenic where the underlying evidence is not available for independent review. ClinVar contains no entries for this variant.	clinvar
PM1	Not met	Residue 362 is not located in a statistically significant mutational hotspot as assessed by cancerhotspots.org (residue_significant: false). While position 362 may lie within the sterol-sensing domain of PTCH1, verified evidence of domain-level benign variation depletion or CSPEC/VCEP confirmation is not available to apply PM1.
PM2	Met	NM_000264.5:c.1085C>T is absent from all population databases: gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Allele frequency is 0.0% in all populations, meeting PM2 at supporting level for a missense variant in an autosomal dominant disorder.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic or likely pathogenic missense variants at the same amino acid residue (Thr362) have been identified in ClinVar to serve as comparator variants. The automated PM5 candidate search returned zero same-residue candidates.	clinvar
PM6	Not met	No reports of de novo occurrence of NM_000264.5:c.1085C>T without confirmation of paternity were identified in the literature or databases.
PP1	Not met	No published data demonstrating co-segregation of NM_000264.5:c.1085C>T with Gorlin syndrome or other PTCH1-associated phenotypes in affected families have been identified.
PP2	Not met	HCI prior probability scores are not available for PTCH1, so a low rate of benign missense variation cannot be computationally established. Without this or equivalent evidence, PP2 cannot be applied.
PP3	Met	REVEL predicts a damaging effect with a score of 0.809 (well above the 0.5 threshold). BayesDel score is 0.454 (borderline, just below 0.5). SpliceAI predicts no significant splice impact (max delta = 0.11). The REVEL meta-predictor, which integrates multiple individual in silico tools, strongly supports a deleterious effect, meeting PP3 at supporting level.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data were provided for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	No reputable source has recently reported NM_000264.5:c.1085C>T as pathogenic. This variant is absent from ClinVar.	clinvar
BA1	Not met	NM_000264.5:c.1085C>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0.0% in all populations, far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	NM_000264.5:c.1085C>T is absent from all population databases (allele frequency 0.0%), well below the BS1 threshold of >0.3% for non-VCEP assessment. BS1 is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No observations of NM_000264.5:c.1085C>T in healthy adult individuals have been reported. The variant is absent from gnomAD, which includes ostensibly healthy population controls.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not met	No well-established functional studies demonstrating no damaging effect of p.Thr362Ile on PTCH1 protein function have been identified.
BS4	Not met	No reports of lack of segregation of NM_000264.5:c.1085C>T with disease in affected families have been identified.
BP1	Not met	BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. PTCH1-associated Gorlin syndrome is caused by both truncating and missense variants; missense variants are a well-established mechanism of pathogenicity in PTCH1. Therefore BP1 is not applicable.
BP2	Not met	No observations of NM_000264.5:c.1085C>T in trans with a pathogenic PTCH1 variant or in cis with a pathogenic variant in any inheritance pattern have been reported. PTCH1-associated disease is autosomal dominant, making the trans scenario required for BP2.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; NM_000264.5:c.1085C>T is a single-nucleotide substitution.
BP4	Not met	REVEL score of 0.809 predicts a damaging effect, not a benign effect. Multiple in silico predictors do not support a benign impact, so BP4 is not met.	revel bayesdel spliceai
BP5	Not met	No observation of NM_000264.5:c.1085C>T in a case with an alternate molecular basis for disease has been reported.
BP6	Not met	No reputable source has reported NM_000264.5:c.1085C>T as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_000264.5:c.1085C>T is a missense variant (p.Thr362Ile), not synonymous.
PM3	N/A	PM3 applies to recessive disorders where a variant is detected in trans with a pathogenic variant. PTCH1-associated Gorlin syndrome is autosomal dominant; PM3 is not applicable.
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants. NM_000264.5:c.1085C>T is a single-nucleotide missense substitution.

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