Variant classification summary

NM_000314.8:c.30_32del

PTEN · NP_000305.3:p.(Ser10del) · NM_000314.8

GRCh37: chr10:89624253 TAGC>T · GRCh38: chr10:87864496 TAGC>T

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PM6 moderate PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Ser10del)

gnomAD AF

ClinVar

Uncertain Significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, below the 0.001% population frequency threshold.

2

PM6 (Moderate): one ClinVar clinical-laboratory record reports presumed de novo occurrence with a PTEN-consistent phenotype; maternity and paternity are unconfirmed, and possible germline mosaicism is flagged for human review.

3

VUS: PM6 (Moderate) plus PM2 (Supporting) matches no established Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule.

Final determination: Under the ClinGen PTEN Expert Panel Version 3.2 criteria-combination framework, PM6 Moderate plus PM2 Supporting matches no final-classification rule and therefore yields VUS.

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	Not met	Not met: p.(Ser10del) is an in-frame single-codon deletion with no premature stop codon, so no nonsense-mediated decay is predicted.	cspec vcep_pvs1_decisiontree_pten
PS1	N/A	Not applicable: PS1 applies only to amino-acid substitutions, and this variant is an in-frame deletion (p.(Ser10del)).	cspec
PS2	Not assessed	Not assessed: confirmed maternity and paternity were not documented, which the PTEN PS2 rule requires for de novo evidence.	cspec clinvar
PS3	Not assessed	Not assessed: no variant-specific result for p.(Ser10del) exists in the Mighell 2018 assay (PS3 requires phosphatase activity <= -1.11).	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: neither a case-control result (odds ratio >2, p<0.05) nor proband phenotype data reaching the specificity score of 1 was available.	cspec clinvar
PM1	Not met	Not met: residue 10 lies outside the PTEN catalytic motifs (WPD loop 90-94, P-loop 123-130, TI-loop 166-168).	cspec PMID:29706350
PM2	Met	Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, below the 0.001% population frequency threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: the PTEN Expert Panel designates PM3 not applicable because PTEN-associated disease is autosomal dominant.	cspec
PM4	Not met	Not met: PM4 requires an in-frame indel affecting a catalytic motif; Ser10 is outside motifs 90-94, 123-130, and 166-168.	cspec
PM5	N/A	Not applicable: PM5 is restricted to missense substitutions, and this variant is an in-frame deletion (p.(Ser10del)).	cspec pm5_candidates
PM6	Met	Met (Moderate): one ClinVar clinical-laboratory record reports presumed de novo occurrence with a PTEN-consistent phenotype, though maternity and paternity are unconfirmed. Flagged for human review: the record is a secondary submission that mentions possible germline mosaicism.	cspec clinvar
PP1	Not assessed	Not assessed: no family co-segregation data was available (supporting strength requires at least 3 informative meioses).	cspec
PP2	N/A	Not applicable: PP2 is restricted to missense variants, and this variant is an in-frame deletion.	cspec
PP3	Not assessed	Not assessed: SpliceAI predicts no splice impact (max delta 0.037), but the required concordant VarSeak prediction is unavailable.	cspec spliceai
PP4	N/A	Not applicable: the PTEN Expert Panel folds phenotype specificity into PS4, so PP4 does not apply.	cspec
PP5	N/A	Not applicable: the ClinVar expert-panel assertion for this variant is Uncertain Significance, not Pathogenic or Likely Pathogenic.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD, well below the 0.056% filtering allele frequency required for BA1.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the variant is absent from gnomAD, with no observed frequency in the BS1 range (0.00043%-0.056%).	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no homozygous observation in a healthy individual was available to support BS2.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay result for p.(Ser10del) was available (BS3 would require phosphatase activity >0 in Mighell 2018).	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no affected relatives lacking the variant were documented, so lack of segregation could not be established.	cspec
BP1	N/A	Not applicable: the PTEN Expert Panel designates BP1 not applicable to PTEN.	cspec
BP2	Not assessed	Not assessed: no phase, cis, or trans observations were available to establish BP2.	cspec
BP3	N/A	Not applicable: explicitly designated not applicable by the PTEN Expert Panel.	cspec
BP4	Not assessed	Not assessed: SpliceAI predicts no splice impact (max delta 0.037), but the required concordant VarSeak result is unavailable.	cspec spliceai
BP5	Not assessed	Not assessed: no evidence of two affected cases with a separate highly penetrant molecular diagnosis was available.	cspec clinvar
BP6	N/A	Not applicable: the ClinVar expert-panel assertion for this variant is Uncertain Significance, not Benign or Likely Benign.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or intronic variants, and this is an exonic in-frame deletion.	cspec

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