Variant classification summary

NM_000264.5:c.2215_2216delinsTT

PTCH1 · NP_000255.2:p.(His739Phe) · NM_000264.5

GRCh37: chr9:98231067 TG>AA · GRCh38: chr9:95468785 TG>AA

Gene: PTCH1 Transcript: NM_000264.5

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

PTCH1

Transcript

NM_000264.5

Protein

NP_000255.2:p.(His739Phe)

gnomAD AF

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): exact variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, with no population frequency observed.

2

BP4 (Supporting): SpliceAI max delta 0.002, well below the 0.1 benign-supporting cutoff, indicating essentially no splicing impact.

3

Synthesis: one supporting pathogenic (PM2) plus one supporting benign (BP4) criterion does not meet any ACMG/AMP combination threshold, yielding a final classification of VUS.

Final determination: Generic ACMG/AMP 2015 fallback: 1 supporting pathogenic (PM2) + 1 supporting benign (BP4) does not meet any P/LP/B/LB combination threshold -> VUS.

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	Not applicable: this is a missense change (p.His739Phe), not a null variant, so no nonsense-mediated decay mechanism applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no pathogenic variant producing the identical amino acid change (p.His739Phe) via a different nucleotide was available for comparison.
PS2	Not assessed	Not assessed: no parental genotype or maternity/paternity data were available to establish a de novo occurrence.
PS3	Not assessed	Not assessed: no functional assay evidence (e.g., minigene, reporter) for this specific variant was identified in the literature.	oncokb PMID:26467025
PS4	Not assessed	Not assessed: no case series or case-control enrichment data showed an excess of this exact variant in affected individuals.
PM1	Not assessed	Not assessed: no PTCH1 domain or hotspot annotation for residue 739 was available; the somatic cancer hotspot query returned no hit.
PM2	Met	Met (supporting): the exact variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, with no population frequency observed.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no biallelic evidence or second pathogenic allele was documented to support recessive inheritance.
PM4	N/A	Not applicable: the variant is a missense substitution, so no protein length change occurs for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different pathogenic missense variant at the same residue (position 739) was identified for comparison.	pm5_candidates
PM6	Not assessed	Not assessed: no suspected de novo occurrence or parental testing data were available.
PP1	Not assessed	Not assessed: no segregation data from affected or unaffected relatives were documented.
PP2	Not assessed	Not assessed: no missense constraint metrics were available to determine whether missense is a common disease mechanism in PTCH1.	pvs1_gene_context
PP3	Not met	Not met: SpliceAI max delta 0.002 is far below the 0.2 high-recall threshold, and no calibrated missense predictor output was available.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype or clinical diagnostic criteria were available to link the variant to the phenotype.
PP5	Not met	Not met: the ClinVar record has zero expert-panel submissions, so no expert-panel classification supports pathogenicity.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, so no allele frequency exceeds the 1% benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: no population allele frequency was observed, so the frequency does not exceed the expected disease prevalence threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no healthy adult homozygotes, hemizygotes, or unaffected carriers of the variant were documented.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay evidence showing normal activity for this variant was identified.	oncokb
BS4	Not assessed	Not assessed: no unaffected tested relatives were described, so non-segregation could not be evaluated.
BP1	Not assessed	Not assessed: no missense constraint data were available to show missense variants are not a common disease mechanism in PTCH1.	pvs1_gene_context
BP2	Not assessed	Not assessed: no observation of the variant in trans or in cis with a pathogenic variant was documented.
BP3	N/A	Not applicable: the variant is a missense substitution, not an in-frame indel in a repetitive region, so this criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): SpliceAI max delta 0.002 is well below the 0.1 benign-supporting cutoff, indicating essentially no splicing impact.	spliceai
BP5	Not assessed	Not assessed: no evidence showed the phenotype is explained by a pathogenic variant in another gene or alternative molecular cause.
BP6	Not met	Not met: the ClinVar record has zero expert-panel submissions, so no expert-panel assertion supports a benign classification.	clinvar
BP7	N/A	Not applicable: this criterion applies to synonymous variants, and this variant changes the protein sequence (p.His739Phe).	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.