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

PTCH1

Transcript

NM_000264.5

HGVS · transcript:coding

NM_000264.5:c.431G>A

Consequence

N/A

GRCh38

chr9:95485838 C>T

GRCh37

chr9:98248120 C>T

Basis 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. ▾

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

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

PM2 → VUS

1 pvs1_gene_context

2 gnomad_v2 ↗gnomad_v4 ↗

3 clinvar ↗

4 revelbayesdelspliceai ↗

5 generic_acmg_combination_rules

Gene diagram · NM_000264.5 · variants mapped to exon structure

PTCH1 NM_000264.5

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

Population frequency

Overall AF

7 / 1,614,112

0.00043%

Highest · European (non-Finnish)

0.00059%

Homozygotes

grpmax FAF

0.00025%

Allele frequency by ancestry — gnomAD v4.1

observed in 1 of 9 groups

Ancestry	Allele count	Frequency	Homozygotes
European (non-Finnish)	7 / 1,180,032	0.00059%	0
Admixed American	0 / 60,022	—	—
European (Finnish)	0 / 64,020	—	—
Amish	0 / 910	—	—
East Asian	0 / 44,878	—	—
Middle Eastern	0 / 6,062	—	—
South Asian	0 / 91,070	—	—
Ashkenazi Jewish	0 / 29,608	—	—
African/African American	0 / 75,000	—	—

“

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.

Overall AF

1 / 251,480

0.0004%

Highest · Admixed American

0.0029%

Homozygotes

Allele frequency by ancestry — gnomAD v2.1

observed in 1 of 8 groups

Ancestry	Allele count	Frequency	Homozygotes
Admixed American	1 / 34,592	0.0029%	0
African/African American	0 / 16,256	—	—
Ashkenazi Jewish	0 / 10,080	—	—
East Asian	0 / 18,394	—	—
European (Finnish)	0 / 21,648	—	—
European (non-Finnish)	0 / 113,754	—	—
Remaining individuals	0 / 6,140	—	—
South Asian	0 / 30,616	—	—

“

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).

“

Not available in gnomAD-Canada v1.0.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 575795)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.583. BayesDel score = 0.230949.

SpliceAI ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Literature · 9 PMIDs triaged · 8 high-priority

9papers screened

Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.

25741868 ↗ functional

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.

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic

BS3PP5PS3PS4

15604628 ↗ case observation

Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.

These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in

PP5PS4

20301330 ↗ case observation

Untitled reference

PP5PS4

21304560 ↗ case observation

Clinical utility gene card for: Gorlin syndrome.

PP5PS4

25394175 ↗ case observation

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.

The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each pract

PP5PS4

26389210 ↗ case observation

Untitled reference

PP5PS4

26389258 ↗ case observation

Untitled reference

PP5PS4

26389333 ↗ case observation

Untitled reference

PP5PS4

28492532 ↗ background review

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

PP5PS4

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots