Classification rationale

BA1BS1BS2BP4BP6BP7 Benign

PTCH1 c.3141T>G

NM_000264.5:c.3141T>G is a synonymous variant in PTCH1 present in gnomAD at an allele frequency of 2.33% with 307 homozygotes in v2.1, meeting BA1 (stand-alone benign) criterion.¹ The variant is classified as Benign in ClinVar by 12 clinical laboratories (Variation ID 255681), meeting BP6 (supporting benign).² As a synonymous variant with no predicted splice impact (SpliceAI max delta = 0.06), BP7 (supporting benign) is met.³ Observation of 307 homozygotes in gnomAD v2.1 meets BS2 (strong benign); homozygous pathogenic PTCH1 variants are incompatible with viability in an autosomal dominant cancer predisposition syndrome.⁴ Per the generic ACMG/AMP 2015 classification rules, a single BA1 (stand-alone benign) criterion is sufficient for a Benign classification, independent of other criteria.⁵ The sole publication identifying this variant (Musani et al., 2013, PMID:23313819) described it as a rare polymorphism found in 1/28 ovarian carcinoma cases with no functional characterization, and concluded its frequency was too low to draw conclusions about a role in ovarian tumor development.⁶

BA1 + BS1 + BS2 + BP4 + BP6 + BP7 → Benign

1 gnomad_v2 ↗gnomad_v4 ↗

2 clinvar ↗

3 spliceai ↗

4 gnomad_v2 ↗

5 generic_acmg_combination_rules

6 PMID:23313819 ↗

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

PTCH1 NM_000264.5

Fetching transcript structure from UCSC…

Applied criteria · 6 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.0122054; MAF= 1.22054%, 19701/1614126 alleles, homozygotes = 872) and has highest observed frequency in the African/African American population (AF= 0.11436; MAF= 11.43604%, 8580/75026 alleles, homozygotes = 500); grpmax FAF= 0.112337.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.0232868; MAF= 2.32868%, 6581/282606 alleles, homozygotes = 307) and has highest observed frequency in the African/African American population (AF= 0.113018; MAF= 11.30184%, 2818/24934 alleles, homozygotes = 163); grpmax FAF= 0.108406.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.018894559669888154, 348/18418 alleles, homozygotes = 10).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

1.2% · 19701 / 1,614,126
872 hom · FAF 11%

African/African American 8580 / 75,026	11% 500 hom
East Asian 4252 / 44,876	9.5% 223 hom
South Asian 3918 / 91,088	4.3% 113 hom
Remaining individuals 1023 / 62,510	1.6% 27 hom
Middle Eastern 58 / 6,060	0.96% 1 hom
Admixed American 449 / 60,024	0.75% 8 hom
European (non-Finnish) 1401 / 1,180,030	0.12%
Ashkenazi Jewish 16 / 29,606	0.054%
European (Finnish) 4 / 63,994	0.0063%

+ 1 not observed (Amish)

gnomAD v2.1

2.3% · 6581 / 282,606
307 hom · FAF 11%

African/African American 2818 / 24,934	11% 163 hom
East Asian 2025 / 19,944	10% 104 hom
South Asian 1327 / 30,610	4.3% 37 hom
Remaining individuals 69 / 7,220	0.96% 1 hom
Admixed American 177 / 35,434	0.5% 2 hom
European (non-Finnish) 161 / 128,988	0.12%
Ashkenazi Jewish 3 / 10,354	0.029%
European (Finnish) 1 / 25,122	0.004%

gnomAD Canada 🇨🇦

1.9% · 348 / 18,418
10 hom · FAF 9.1%

indel · split

African/African American 109 / 1,020	11% 3 hom
East Asian 131 / 1,338	9.8% 7 hom
South Asian 61 / 1,362	4.5%
Middle Eastern 3 / 144	2.1%
Remaining individuals 14 / 1,138	1.2%
Latino/Admixed American 7 / 838	0.84%
European (non-Finnish) 23 / 11,738	0.2%

+ 2 not observed (Ashkenazi Jewish, European (Finnish))

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (11 clinical laboratories) and as benign (1 clinical laboratory). (ClinVarID = 255681)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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; COSV59476925, n = 6 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

18502968 ↗ PTCH1 and SMO gene alterations in keratocystic odontogenic tumors. CLINVAR

21304560 ↗ Clinical utility gene card for: Gorlin syndrome. CLINVAR

23313819 ↗ PTCH1 gene polymorphisms in ovarian tumors: potential protective role of c.3944T allele. 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