Classification rationale

PM2 VUS

PDCD10 c.345T>G

NM_007217.3:c.345T>G (p.Ser115Arg) in PDCD10 is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada), meeting PM2 at a supporting level.¹ The only criterion met is PM2 (supporting); no other pathogenic or benign criteria are satisfied. According to the generic ACMG/AMP 2015 combination rules (PMID:25741868), a single supporting criterion is insufficient for classification as likely pathogenic or likely benign. The variant remains a variant of uncertain significance (VUS).²

PM2 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 generic_acmg_combination_rules

Gene diagram · NM_007217.3 · variants mapped to exon structure

PDCD10 NM_007217.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 23 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

NM_007217.3:c.345T>G is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency = 0.0), well below the 0.1% threshold for a rare variant in a gene associated with autosomal dominant familial cerebral cavernous malformations. Absence from large population databases supports pathogenicity at a supporting level.

Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes/genomes)Absent from gnomAD-Canada v1.0 (HostSeq genomes)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied · 23 not met · 0 not assessed

Pathogenic

PVS1 NM_007217.3:c.345T>G is a missense variant (p.Ser115Arg) in exon 6 of PDCD10.

PS1 No previously established pathogenic variant with the same amino acid change (p.Ser115Arg) at this position has been reported in ClinVar or the literature.

PS2 No de novo observation with confirmed paternity and maternity has been reported for this variant.

PS3 No well-established functional studies demonstrating a damaging effect for NM_007217.3:c.345T>G (p.Ser115Arg) have been identified.

PS4 No case-control or cohort data demonstrate enrichment of this variant in affected individuals compared to controls.

PM1 Residue Ser115 is not located in a statistically significant mutational hotspot per cancerhotspots.org.

PM5 No comparator missense variants at residue Ser115 have been identified as pathogenic in ClinVar.

PM6 No assumed de novo observation (without confirmed paternity/maternity) has been reported for this variant.

PP1 No cosegregation data with disease in multiple affected family members has been reported for this variant.

PP2 HCI prior probability data is not available for PDCD10.

PP3 Computational evidence is inconsistent and does not provide multiple lines of support for a deleterious effect.

PP4 No patient phenotype or family history data are available for this case.

PP5 No reputable source (ClinVar submitter, clinical laboratory, or publication) has reported this variant as pathogenic.

Benign

BA1 The variant is absent from all gnomAD population databases (allele frequency = 0.0), far below the 1% BA1 threshold.

BS1 The variant is absent from all gnomAD population databases (allele frequency = 0.0), far below the 0.3% BS1 threshold.

BS2 No observation of this variant in a healthy adult individual has been reported.

BS3 No well-established functional studies demonstrating a benign effect for p.Ser115Arg have been identified.

BS4 No segregation data are available to demonstrate lack of segregation with disease in affected family members.

BP1 While PDCD10 loss of function is an established mechanism for familial cerebral cavernous malformations, there is insufficient evidence to conclude that primarily truncating variants cause disease to the exclusion of missense variants.

BP2 No phasing data are available to determine whether this variant has been observed in trans with a pathogenic variant in PDCD10 (autosomal dominant FCCM) or in cis with a pathogenic variant.

BP4 Multiple lines of computational evidence do not uniformly suggest no impact.

BP5 No evidence that this variant has been observed in a case with an alternate molecular basis for disease.

BP6 No reputable source has reported this variant as benign.

N/A · 4 PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.649. BayesDel score = 0.175349.

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

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

Re-run this variant?