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).1 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.2 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.3 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).4 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.5
PTCH1
Final classification
VUS
PTCH1 c.431G>A · p.Arg144His
PTCH1
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).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2
VUS
PTCH1 c.431G>A
PM2
→
VUS
Gene diagram
· NM_000264.5 · variants mapped to exon structure
PTCH1
NM_000264.5
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 22 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: AF = 3.98e-6 (1/251480 alleles0 homozygotes)
Assessed · not applied
Pathogenic
PS1
No different nucleotide change resulting in p.Arg144His has been reported as pathogenic in ClinVar or the literature reviewed for this case.
PS2
No de novo occurrence data (with confirmed maternity/paternity) are available for this variant.
PS3
No well-established in vitro or in vivo functional studies demonstrating a damaging effect on PTCH1 for this specific variant are available.
PS4
No case-control or odds-ratio data comparing variant prevalence in affected versus unaffected individuals are available.
PM1
Arg144 is not located in a statistically significant mutational hotspot for PTCH1.
PM5
No different missense change at Arg144 (p.Arg144Gly, p.Arg144Cys, etc.) has been established as pathogenic.
PM6
No de novo occurrence data (without confirmation of paternity/maternity) are available for this variant.
PP1
No segregation data demonstrating co-segregation of this variant with disease in multiple affected family members are available.
PP2
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
Computational evidence is mixed and does not provide multiple concordant lines supporting a deleterious effect.
PP4
Insufficient clinical phenotypic specificity is documented for the patient(s) carrying this variant.
PP5
No reputable source (e.g., expert panel, clinical laboratory with published strong evidence) has reported this variant as pathogenic.
Benign
BA1
gnomAD allele frequency (~4e-6) is far below the >1% BA1 threshold.
BS1
gnomAD allele frequency (~4e-6) is far below the >0.3% BS1 threshold.
BS2
No homozygotes for this variant have been observed in gnomAD.
BS3
No well-established functional studies demonstrating no damaging effect for this specific variant are available.
BS4
No segregation data are available to evaluate lack of segregation of this variant with disease in affected family members.
BP1
PTCH1 is not a gene where primarily truncating variants cause disease.
BP2
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.
BP4
Computational evidence is mixed and does not provide multiple concordant lines of evidence suggesting no impact.
BP5
No evidence is available that a case harboring this variant has an alternate molecular basis for disease.
BP6
Although Labcorp Genetics (Invitae) classifies this variant as Likely Benign (SCV000826756), the evidence supporting that classification is not available for independent evaluation.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.33675e-06; MAF= 0.00043%, 7/1614112 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.93204e-06; MAF= 0.00059%, 7/1180032 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.97646e-06; MAF= 0.00040%, 1/251480 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89084e-05; MAF= 0.00289%, 1/34592 alleles, homozygotes = 0).
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00043%
· 7 / 1,614,112
0 hom · FAF 0.00025%
0 hom · FAF 0.00025%
European (non-Finnish) 7 / 1,180,032 |
0.00059% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 251,480
0 hom
0 hom
Admixed American 1 / 34,592 |
0.0029% |
+ 7 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 575795)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.583. BayesDel score = 0.230949.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTCH1, a tumor suppressor and inhibitor of the hedgehog pathway, is recurrently mutated in basal cell carcinoma.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59469010, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR