Variant classification summary

NM_000264.5:c.1641C>T

PTCH1 · NP_000255.2:p.(Ser547=) · NM_000264.5

GRCh37: chr9:98238403 G>A · GRCh38: chr9:95476121 G>A

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.(Ser547=)

gnomAD AF

0.011250557786702364 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000264.5:c.1641C>T is a synonymous variant (p.Ser547=) in PTCH1 with no predicted impact on splicing (SpliceAI max delta=0.00).

2

This variant is present at high frequency in population databases: gnomAD v2.1 AF=0.798% (2242/281002 alleles, including 17 homozygotes) and v4.1 AF=1.125% (18153/1613520 alleles, including 125 homozygotes), exceeding the BA1 (>1%) and BS1 (>0.3%) thresholds for an autosomal dominant disorder with full penetrance expected at an early age.

3

The observation of 17 homozygotes in gnomAD v2.1 and 125 homozygotes in gnomAD v4.1 is incompatible with a fully penetrant autosomal dominant condition; this alone is strong evidence for a benign classification (BS2).

4

ClinVar classifies this variant as Benign based on submissions from 14 clinical laboratories; this represents a reputable source reporting a benign classification (BP6).

5

The variant was identified as a non-pathogenic synonymous polymorphism (rs2066830, p.S547S) in a study of 78 sporadic medulloblastoma cases and in ovarian tumor/control cohorts, consistent with a benign interpretation.

6

Computational evidence (SpliceAI) predicts no splicing impact; combined with its synonymous nature, this supports a benign interpretation (BP4, BP7).

7

The BA1 criterion is met at stand-alone benign strength: allele frequency >1% in multiple gnomAD populations is incompatible with a highly penetrant dominant disorder. Per ACMG/AMP 2015 combination rules, meeting BA1 alone is sufficient for a Benign classification regardless of other criteria.

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	PVS1 applies to null variants (nonsense, frameshift, canonical ±1,2 splice sites). NM_000264.5:c.1641C>T is a synonymous variant (p.Ser547=) and does not fall into any PVS1 null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	N/A	PS1 requires the same amino acid change as a previously established pathogenic variant. c.1641C>T is a synonymous variant with no amino acid change (p.Ser547=).
PS2	Not assessed	No de novo observation (with confirmed paternity and maternity) has been reported for NM_000264.5:c.1641C>T in the reviewed literature.
PS3	Not assessed	No well-established in vitro or in vivo functional studies were identified that directly assess the functional impact of NM_000264.5:c.1641C>T.
PS4	Not met	The variant is common in the general population (gnomAD v2.1 AF=0.798%, v4.1 AF=1.125%) and is classified as Benign in ClinVar. There is no evidence of statistically significant enrichment in affected individuals versus controls. In PMID:23313819, the variant was observed in dermoid and control samples but not enriched in ovarian tumors.	gnomad_v2 gnomad_v4 clinvar PMID:23313819
PS5	Not met	No reputable source reports NM_000264.5:c.1641C>T as pathogenic. ClinVar classifies this variant as Benign (14 clinical laboratories), and PMID:21188540 explicitly lists it among non-pathogenic PTCH1 variants.	clinvar PMID:21188540
PM1	Not met	The variant does not lie within a statistically significant mutational hotspot (residue_significant=false) and no critical functional domain without benign variation has been identified for this position. The PTCH1 hotspots analysis confirms the variant is not in a known hotspot.
PM2	Not met	PM2 requires absence from population controls (or AF <0.1% in non-VCEP framework). NM_000264.5:c.1641C>T is present in gnomAD v2.1 at AF=0.798% (2242/281002 alleles, 17 homozygotes) and v4.1 at AF=1.125% (18153/1613520 alleles, 125 homozygotes), far exceeding the 0.1% threshold.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a different missense change at the same residue as a known pathogenic missense variant. c.1641C>T is a synonymous variant producing no amino acid change; no missense residue context is available.	pm5_candidates
PM6	Not assessed	No de novo observation (without confirmation of paternity and maternity) has been reported for NM_000264.5:c.1641C>T.
PP1	Not assessed	No co-segregation data for NM_000264.5:c.1641C>T with disease in affected families was identified in the reviewed literature.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. NM_000264.5:c.1641C>T is a synonymous variant, not a missense change.
PP3	Not met	Multiple lines of computational evidence do NOT support a deleterious effect. SpliceAI predicts no splicing impact (max delta=0.00). REVEL and BayesDel scores are unavailable. This is a synonymous variant with no in silico evidence of functional disruption.	spliceai
PP4	Not assessed	No specific patient phenotype data were available for NM_000264.5:c.1641C>T to assess whether the patient's phenotype or family history is highly specific for PTCH1-related disease.
PP5	Not met	Reputable sources do not report NM_000264.5:c.1641C>T as pathogenic. ClinVar classifies the variant as Benign (14 clinical laboratories). PMID:21188540 explicitly lists this variant among non-pathogenic synonymous PTCH1 variants.	clinvar PMID:21188540
BA1	Met	NM_000264.5:c.1641C>T has an allele frequency exceeding 1% in gnomAD. In v4.1 the total AF is 1.125% (18153/1613520 alleles) and the grpmax FAF is 1.38%. In v2.1 the European (non-Finnish) subpopulation AF is 1.37% (1756/128296 alleles) and the grpmax FAF is 1.32%. These frequencies exceed the BA1 >1% threshold and are incompatible with a highly penetrant autosomal dominant disorder (Gorlin syndrome).	gnomad_v2 gnomad_v4
BS1	Met	NM_000264.5:c.1641C>T has an allele frequency exceeding 0.3% in gnomAD. In v2.1 the total AF is 0.798% (2242/281002 alleles) and in v4.1 the total AF is 1.125% (18153/1613520 alleles). These frequencies are substantially above the 0.3% BS1 threshold for a highly penetrant dominant disorder.	gnomad_v2 gnomad_v4
BS2	Met	NM_000264.5:c.1641C>T has been observed in the homozygous state in multiple individuals in gnomAD: 17 homozygotes in v2.1 and 125 homozygotes in v4.1. For a fully penetrant autosomal dominant disorder (Gorlin syndrome), the presence of healthy adult homozygotes in population databases is strong evidence for a benign classification.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no damaging effect were identified for NM_000264.5:c.1641C>T specifically. The variant is synonymous and computational evidence (SpliceAI delta=0.00) suggests no splicing impact, which is consistent with a benign interpretation but does not constitute the well-established functional evidence required for BS3.	spliceai
BS4	Not assessed	No family-based lack of segregation data were identified for NM_000264.5:c.1641C>T. The available literature (PMID:21188540, PMID:29498494) does not report segregation analysis for this specific variant.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants cause disease. NM_000264.5:c.1641C>T is a synonymous variant, not a missense change.
BP2	Not assessed	No data were identified showing NM_000264.5:c.1641C>T observed in trans with a known pathogenic PTCH1 variant. PTCH1-related disorders are autosomal dominant, making trans configuration less relevant, but BP2 was not formally assessed due to absence of co-occurrence data.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions. NM_000264.5:c.1641C>T is a single-nucleotide substitution, not an in-frame indel.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splicing impact (max delta score=0.00 for all acceptor and donor gain/loss predictions). This is a synonymous variant (p.Ser547=) at a position where no splicing disruption is predicted. While REVEL and BayesDel scores are unavailable, the absence of any in silico evidence of deleteriousness supports a benign interpretation.	spliceai
BP5	Not assessed	No case with an alternate molecular basis for disease was identified that harbors NM_000264.5:c.1641C>T. No evidence was found of this variant occurring in a patient whose phenotype is explained by a different pathogenic variant.
BP6	Met	A reputable source (ClinVar) classifies NM_000264.5:c.1641C>T as Benign. Fourteen clinical laboratories have submitted Benign classifications, with one additional likely benign and one additional benign submission. While no expert panel has reviewed this variant, the consistent classification across multiple clinical laboratories provides supporting evidence for a benign interpretation.	clinvar
BP7	Met	NM_000264.5:c.1641C>T is a synonymous variant (p.Ser547=) at a nucleotide position with no predicted splicing impact. SpliceAI predicts a max delta score of 0.00, indicating the variant does not alter any splice site. In the absence of evidence for an effect on splicing, synonymous variants are generally considered likely benign under BP7.	spliceai

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