Variant classification summary

NM_000264.5:c.3141T>G

PTCH1 · NP_000255.2:p.(Leu1047=) · NM_000264.5

GRCh37: chr9:98220322 A>C · GRCh38: chr9:95458040 A>C

Gene: PTCH1 Transcript: NM_000264.5

Final call

Benign

BA1 stand-alone benign BS1 strong benign BS2 strong benign BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

PTCH1

Transcript

NM_000264.5

Protein

NP_000255.2:p.(Leu1047=)

gnomAD AF

0.012205366867270586 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

The variant is classified as Benign in ClinVar by 12 clinical laboratories (Variation ID 255681), meeting BP6 (supporting benign).

3

As a synonymous variant with no predicted splice impact (SpliceAI max delta = 0.06), BP7 (supporting benign) is met.

4

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.

5

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.

6

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

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	NM_000264.5:c.3141T>G is a synonymous variant (p.Leu1047=) that does not alter the protein sequence. PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1/2 splice sites) and is not applicable to synonymous substitutions.	pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies when the variant produces the same amino acid change as a previously established pathogenic variant. NM_000264.5:c.3141T>G is synonymous (p.Leu1047=) and produces no amino acid change, rendering this criterion inapplicable.
PS2	Not assessed	No de novo data are available for this variant. PS2 requires confirmed de novo occurrence in a patient with the disease and no family history.
PS3	Not met	No well-established functional studies demonstrate a damaging effect for NM_000264.5:c.3141T>G. The one study that identified the variant (Musani et al., 2013) described it as a rare polymorphism with no functional characterization. The variant's high population frequency further argues against a damaging functional effect.	PMID:23313819
PS4	Not met	The variant is common in the general population (gnomAD v2.1 AF=2.33%, 307 homozygotes), making it statistically incompatible with significant enrichment in affected individuals. PS4 requires significantly increased prevalence in cases versus controls.	gnomad_v2 gnomad_v4
PS5	Not met	ClinVar classifies this variant as Benign (12 clinical laboratories, criteria provided). No reputable source has recently classified it as pathogenic. PS5 requires a reputable source to report the variant as pathogenic.	clinvar
PM1	Not met	The variant does not lie in a statistically significant mutational hot spot in PTCH1. Evidence from cancer hotspot databases confirms c.3141T>G is not in a recognized functional domain hot spot.
PM2	Not met	The variant is present in gnomAD at high frequency (AF=2.33% in v2.1, 307 homozygotes), far exceeding the PM2 absence threshold of <0.1%. This criterion is clearly not met.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 applies when a novel missense change occurs at the same residue as a known pathogenic missense variant. NM_000264.5:c.3141T>G is a synonymous variant and does not alter the amino acid at position 1047.	pm5_candidates
PM6	Not assessed	No de novo data are available for this variant. PM6 requires a de novo observation without confirmation of paternity and maternity.
PP1	Not assessed	No cosegregation data are available for this variant. PP1 requires cosegregation of the variant with disease in multiple affected family members.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. NM_000264.5:c.3141T>G is synonymous (p.Leu1047=), not a missense change.
PP3	Not met	SpliceAI predicts no significant splicing impact (max delta score = 0.06). REVEL and BayesDel scores are unavailable. No in silico evidence supports a deleterious effect for this synonymous variant.	spliceai
PP4	Not assessed	No data on the patient's phenotype or family history are available. PP4 requires a highly specific phenotype for the disease with a single genetic etiology.
PP5	Not met	ClinVar classifies this variant as Benign by 12 clinical laboratories, not pathogenic. PP5 requires a reputable source to have recently classified the variant as pathogenic.	clinvar
BA1	Met	The variant is present in gnomAD v2.1 at an allele frequency of 2.33% (grpmax filtering AF=10.84% in the African/African American population), far exceeding the BA1 threshold of >1%. A total of 307 homozygotes are observed in gnomAD v2.1. In gnomAD v4.1, AF=1.22% with 872 homozygotes. For an autosomal dominant disorder (Gorlin syndrome) with high penetrance, this frequency is incompatible with pathogenicity.	gnomad_v2 gnomad_v4
BS1	Met	The variant allele frequency of 2.33% in gnomAD v2.1 exceeds the BS1 threshold of >0.3% for a dominantly inherited disorder. This frequency alone is sufficient strong evidence for a benign classification, though it is subsumed by the stand-alone BA1 criterion.	gnomad_v2 gnomad_v4
BS2	Met	The variant is observed in the homozygous state in 307 individuals in gnomAD v2.1 and 872 in gnomAD v4.1. For PTCH1, which causes Gorlin syndrome (an autosomal dominant disorder with high penetrance and significant morbidity), observation of homozygosity in healthy population databases is incompatible with pathogenicity. A homozygous pathogenic PTCH1 variant would be expected to be lethal or cause severe disease.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional studies directly demonstrate that NM_000264.5:c.3141T>G has no damaging effect on protein function or splicing. The ClinVar submission from LabCorp notes that 5/5 in silico programs predict no splicing effect, but no formal functional studies were published. The extreme population frequency, however, serves as strong indirect evidence of no functional impact.
BS4	Not assessed	No segregation data are available for this variant. BS4 requires lack of cosegregation in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants cause disease. NM_000264.5:c.3141T>G is synonymous, not missense.
BP2	Not assessed	No data are available regarding observation of this variant in trans with a known pathogenic PTCH1 variant. BP2 requires observation in trans with a pathogenic variant for a dominantly inherited disorder.
BP4	Met	SpliceAI predicts no significant splicing impact (max delta score = 0.06, well below the clinically significant threshold of 0.1). Multiple in silico splicing prediction tools cited in the ClinVar submission concur that the variant does not affect normal splicing. This supports a benign interpretation for this synonymous variant.	spliceai
BP5	Not assessed	No data are available regarding an alternate molecular basis for disease in individuals carrying this variant. BP5 requires identification of an alternative causative variant in a case where this variant was also found.
BP6	Met	This variant is classified as Benign in ClinVar by 12 clinical diagnostic laboratories (Variation ID 255681), with criteria provided. Multiple submitters independently reached a benign classification, consistent with a reputable source classification for BP6.	clinvar
BP7	Met	NM_000264.5:c.3141T>G is a synonymous variant (p.Leu1047=). SpliceAI predicts no splicing impact (max delta = 0.06, well below 0.1 threshold). The high population frequency (AF=2.33%) is inconsistent with evolutionary conservation at this position. These findings satisfy BP7 criteria for a synonymous variant with no predicted impact on splicing or protein function.	spliceai gnomad_v2

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