NM_000264.5:c.536T>C

PTCH1 · NP_000255.2:p.(Leu179Pro) · NM_000264.5

GRCh37: chr9:98248015 A>G · GRCh38: chr9:95485733 A>G

Gene: PTCH1 Transcript: NM_000264.5

Final call

VUS

PM1 moderate PM2 supporting

Variant details

Gene

PTCH1

Transcript

NM_000264.5

Protein

NP_000255.2:p.(Leu179Pro)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM1 (moderate): p.Leu179Pro is located within the first extracellular loop (aa 115–210) of PTCH1, a critical Hedgehog ligand-binding domain that is a well-established mutational hotspot in Gorlin syndrome.

PM2 (supporting): NM_000264.5:c.536T>C is absent from gnomAD v2.1 and v4.1 population databases (allele frequency 0%), consistent with a rare variant.

Overall, one moderate criterion (PM1) and one supporting criterion (PM2) are met. Per the ACMG/AMP 2015 generic combination rules (PMID:25741868), this combination is insufficient to reach Likely Pathogenic (minimum: 3 moderate, 2 moderate + 2 supporting, or 1 moderate + 4 supporting). 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.536T>C is a missense variant (p.Leu179Pro) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No evidence was identified of a different nucleotide change at codon 179 resulting in the same p.Leu179Pro amino acid substitution that has been classified as pathogenic.	clinvar
PS2	Not met	No de novo occurrence with confirmed paternity and maternity was identified for this variant.	clinvar
PS3	Not met	No well-established functional studies demonstrating a damaging effect were identified for NM_000264.5:c.536T>C (p.Leu179Pro).	oncokb
PS4	Not met	No case-control studies demonstrating statistically significant enrichment of this variant in affected individuals versus controls were identified.	gnomad_v2 gnomad_v4 clinvar
PS5	Not met	No reputable source has recently reported this variant as pathogenic with unavailable evidence.	clinvar
PM1	Met	The variant p.Leu179Pro is located at amino acid 179 within the first extracellular loop (approximately aa 115–210) of PTCH1, a critical Hedgehog ligand-binding domain where pathogenic missense variants cluster in Gorlin syndrome. This domain is a well-established mutational hotspot for this disorder.
PM2	Met	NM_000264.5:c.536T>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with an allele frequency well below the 0.1% threshold for PM2 in non-VCEP ACMG/AMP assessment.	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic missense variant has been established at the same amino acid residue (Leu179) via a different nucleotide change.	pm5_candidates
PM6	Not met	No assumed de novo observation (without confirmation of paternity and maternity) was identified for this variant.	clinvar
PP1	Not met	No cosegregation data in multiple affected family members is available for this variant.
PP2	Not assessed	Missense constraint metrics for PTCH1 (e.g., gnomAD missense Z-score or o/e ratio) were not retrieved; the low rate of benign missense variation required by PP2 cannot be evaluated without this data.
PP3	Not met	Multiple lines of computational evidence do not converge on a deleterious prediction: SpliceAI predicts no splicing impact (max delta score 0.02), BayesDel score is intermediate (0.448), and REVEL is unavailable. Insufficient computational support for PP3.	spliceai bayesdel
PP4	Not assessed	No patient-specific phenotype or family history data were provided with this case; phenotypic specificity for Gorlin syndrome cannot be evaluated.
PP5	Not met	No reputable source has reported this variant as pathogenic with unavailable evidence.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1; the allele frequency does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD v2.1 and v4.1; the allele frequency does not exceed the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	This variant has not been observed in healthy adults at an age where Gorlin syndrome would be fully penetrant.
BS3	Not met	No well-established functional studies demonstrating a neutral or benign effect were identified for NM_000264.5:c.536T>C.	oncokb
BS4	Not met	No documented lack of segregation in affected family members was identified; no unaffected carriers have been reported.
BP1	Not met	Missense variants in PTCH1, particularly those in the extracellular loops, are a well-established pathogenic mechanism for Gorlin syndrome. PTCH1 is not a gene where primarily truncating variants cause disease; missense variants are a common disease mechanism.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a known pathogenic PTCH1 variant in a healthy individual was identified.
BP3	N/A	Variant is a missense substitution, not an in-frame insertion or deletion in a repetitive region.
BP4	Not met	Multiple lines of computational evidence do not converge on a benign prediction: SpliceAI shows no splicing impact (delta 0.02), but BayesDel is intermediate (0.448) and REVEL is unavailable. Insufficient support for BP4.	spliceai bayesdel
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease was identified.
BP6	Not met	No reputable source has reported this variant as benign with unavailable evidence.	clinvar
BP7	N/A	NM_000264.5:c.536T>C is a missense variant (p.Leu179Pro), not a synonymous variant with no predicted splice impact.
PM3	N/A	PTCH1-associated Gorlin syndrome is autosomal dominant with haploinsufficiency as the disease mechanism; biallelic observations are not the standard disease mechanism for PM3 assessment.
PM4	N/A	Variant is a single nucleotide substitution (c.536T>C), not a protein length-altering change (in-frame deletion/insertion, stop-loss, or initiation codon variant).

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