NM_000264.5:c.431G>A

PTCH1 · NP_000255.2:p.(Arg144His) · NM_000264.5

GRCh37: chr9:98248120 C>T · GRCh38: chr9:95485838 C>T

Gene: PTCH1 Transcript: NM_000264.5

Final call

VUS

PM2 supporting

Variant details

Gene

PTCH1

Transcript

NM_000264.5

Protein

NP_000255.2:p.(Arg144His)

gnomAD AF

4.33674986618029e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000264.5(PTCH1):c.431G>A (p.Arg144His) is a missense variant in PTCH1, a gene associated with autosomal dominant Gorlin syndrome (nevoid basal cell carcinoma syndrome).

This variant is exceedingly rare in population databases, with an allele frequency of approximately 4.0e-6 in both gnomAD v2.1 (1/251,480 alleles) and v4.1 (7/1,614,112 alleles), and no homozygotes have been observed.

The variant has been reported in ClinVar (Variation ID 575795) as Uncertain Significance by three clinical laboratories and as Likely Benign by one laboratory; no expert panel classification is available.

Computational predictors are mixed: REVEL scores 0.583 (borderline), BayesDel scores 0.231 (benign-leaning), and SpliceAI predicts no splicing impact (max delta 0.05).

No variant-specific functional studies, segregation data, de novo observations, case-control data, or reputable pathogenic classifications are available for this variant.

Applying generic ACMG/AMP 2015 criteria (PMID:25741868), only PM2 (supporting) is met. With a single supporting pathogenic criterion and no benign criteria met, the final classification is 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
BP3	N/A	c.431G>A is a single-nucleotide substitution, not an in-frame indel. BP3 applies to in-frame deletions/insertions in a repetitive region without a known function.
PM3	N/A	PTCH1-associated Gorlin syndrome is an autosomal dominant disorder. PM3 (variant in trans with a pathogenic variant) applies to recessive disorders.
PM4	N/A	c.431G>A is a single-nucleotide missense substitution, not a protein-length-altering variant (in-frame deletion/insertion or stop-loss).
PVS1	N/A	c.431G>A (p.Arg144His) is a missense variant. PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, or exon-level deletions). This variant falls into the 'other' variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798) and does not meet any default null-variant criteria.	pvs1_generic_framework
PS1	Not met	No different nucleotide change resulting in p.Arg144His has been reported as pathogenic in ClinVar or the literature reviewed for this case.	clinvar
PS2	Not met	No de novo occurrence data (with confirmed maternity/paternity) are available for this variant. Reviewed publications contain no variant-specific de novo reports.
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrating a damaging effect on PTCH1 for this specific variant are available. OncoKB reports unknown oncogenic effect, and none of the reviewed publications contain variant-specific functional assay data.	oncokb
PS4	Not met	No case-control or odds-ratio data comparing variant prevalence in affected versus unaffected individuals are available. Reviewed publications are general practice guidelines, PDQ summaries, and methodology papers that do not provide variant-specific observational data.
PS5	Not met	No different missense change at Arg144 has been established as pathogenic. Automated PM5 comparator candidate harvesting returned no candidates at this residue.	pm5_candidates
PM1	Not met	Arg144 is not located in a statistically significant mutational hotspot for PTCH1. Independent evidence localizing codon 144 to a critical and well-established functional domain was not available in the evidence record.
PM2	Met	This variant is exceedingly rare in population databases: gnomAD v2.1 allele frequency = 3.98e-6 (1/251,480 alleles), gnomAD v4.1 AF = 4.34e-6 (7/1,614,112 alleles), both well below the 0.1% (0.001) threshold. No homozygotes have been observed.	gnomad_v2 gnomad_v4
PM5	Not met	No different missense change at Arg144 (p.Arg144Gly, p.Arg144Cys, etc.) has been established as pathogenic. Automated PM5 comparator candidate harvesting returned no eligible comparators.	pm5_candidates
PM6	Not met	No de novo occurrence data (without confirmation of paternity/maternity) are available for this variant. Reviewed literature contains no de novo reports.
PP1	Not met	No segregation data demonstrating co-segregation of this variant with disease in multiple affected family members are available.
PP2	Not met	Although PTCH1 missense variants are a well-established disease mechanism in Gorlin syndrome, gene-level missense constraint metrics (e.g., gnomAD missense Z-score, regional constraint) were not available in the evidence record to establish a low rate of benign missense variation, which is required to meet PP2 under generic ACMG/AMP criteria.
PP3	Not met	Computational evidence is mixed and does not provide multiple concordant lines supporting a deleterious effect. REVEL = 0.583 (borderline, below typical high-confidence pathogenic thresholds), BayesDel = 0.231 (benign-leaning), and SpliceAI max delta = 0.05 (no predicted splicing impact). A single borderline REVEL score does not constitute multiple lines of computational support.	revel bayesdel spliceai
PP4	Not met	Insufficient clinical phenotypic specificity is documented for the patient(s) carrying this variant. No detailed phenotype description highly specific for Gorlin syndrome with a single genetic etiology is available in the evidence record.
PP5	Not met	No reputable source (e.g., expert panel, clinical laboratory with published strong evidence) has reported this variant as pathogenic. ClinVar reports three submitters as VUS and one as Likely Benign. The cited PMIDs (25741868, 28492532) are general classification methodology papers that do not assess this variant specifically.	clinvar PMID:25741868 PMID:28492532
BA1	Not met	gnomAD allele frequency (~4e-6) is far below the >1% BA1 threshold. This variant is extremely rare, not common.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD allele frequency (~4e-6) is far below the >0.3% BS1 threshold. This variant is extremely rare, not a benign-standing polymorphism.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygotes for this variant have been observed in gnomAD. For a fully penetrant dominant condition (Gorlin syndrome), BS2 requires observation in a healthy adult homozygous state, which is not present.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating no damaging effect for this specific variant are available. OncoKB reports unknown oncogenic effect with no variant-specific functional data.	oncokb
BS4	Not met	No segregation data are available to evaluate lack of segregation of this variant with disease in affected family members.
BP1	Not met	PTCH1 is not a gene where primarily truncating variants cause disease. Pathogenic missense variants in PTCH1 are a well-established mechanism of Gorlin syndrome, as supported by the germline disease literature reviewed in the PVS1 gene-level context.	pvs1_gene_context
BP2	Not met	No data are available regarding the occurrence of this variant in trans with a known pathogenic variant (relevant for recessive disorders) or in cis with a pathogenic variant. Additionally, Gorlin syndrome is an autosomal dominant condition.
BP4	Not met	Computational evidence is mixed and does not provide multiple concordant lines of evidence suggesting no impact. REVEL = 0.583 is in a pathogenic-leaning range, BayesDel = 0.231 is benign-leaning but not strongly so. SpliceAI shows no splicing impact, but this does not constitute multiple lines of benign computational evidence.	revel bayesdel spliceai
BP5	Not met	No evidence is available that a case harboring this variant has an alternate molecular basis for disease. BP5 requires identification of an alternative causative variant in a proband with this variant.
BP6	Not met	Although Labcorp Genetics (Invitae) classifies this variant as Likely Benign (SCV000826756), the evidence supporting that classification is not available for independent evaluation. BP6 requires a reputable source (typically an expert panel or multiple laboratories with strong consensus) to report the variant as benign with evidence not independently available. A single clinical laboratory submission citing only a general classification methodology paper (PMID:28492532, Sherloc) does not meet this threshold.	clinvar PMID:28492532
BP7	N/A	c.431G>A is a missense variant (p.Arg144His), not a synonymous (silent) variant. BP7 is reserved for synonymous variants with no predicted splicing impact.

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.