Variant classification summary

NM_000314.8:c.700_701del

PTEN · NP_000305.3:p.(Arg234GlyfsTer8) · NM_000314.8

GRCh37: chr10:89717674 ACG>A · GRCh38: chr10:87957917 ACG>A

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Arg234GlyfsTer8)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.700_701del is a frameshift deletion in PTEN exon 7 producing p.Arg234GlyfsTer8, a premature termination codon predicted to undergo nonsense-mediated decay at or 5' to the p.D375 (c.1121) threshold, meeting PVS1 at very-strong strength per the PTEN expert panel decision tree.

2

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength (<0.001% allele frequency).

3

The variant is absent from ClinVar; no functional, de novo, segregation, or case-level evidence is available to support or refute additional criteria.

4

Under the PTEN VCEP combination rules, a single PVS1 (very strong) criterion is sufficient for a Pathogenic classification (Rule 1, Condition 1).

Final determination: Rule20 in the ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Pathogenic.

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	Met	Frameshift deletion (NM_000314.8:c.700_701del, p.Arg234GlyfsTer8) introduces a premature termination codon in exon 7 at approximately p.241, 5' to the p.D375 (c.1121) NMD threshold, and is predicted to undergo nonsense-mediated decay in the biologically relevant transcript NM_000314.8. PTEN loss of function is an established mechanism of PTEN hamartoma tumor syndrome; per the PTEN PVS1 decision tree this is assigned full-strength PVS1.	vcep_pvs1_decisiontree_pten cspec pvs1_gene_context
PS1	Not met	No previously established pathogenic variant with the same amino acid change (p.Arg234GlyfsTer8) was identified, and the variant is absent from ClinVar, so PS1 cannot be applied.	clinvar
PS2	Not met	No de novo observation (with confirmed maternity and paternity) for this variant has been reported.
PS3	Not met	No variant-specific experimental functional data exist. The PTEN VCEP PS3_Moderate path (Mighell et al. 2018 saturation mutagenesis, mmc2.xlsx) interrogates missense variants only and does not cover this frameshift. OncoKB's 'Likely Oncogenic / loss-of-function' annotation is a curated bioeffect prediction, not experimental functional evidence for this variant.	vcep_mmc2 oncokb
PS4	Not met	No proband or affected-individual counts are available; the variant is absent from ClinVar and no case-control data exist.	clinvar
PS5	N/A	PS5 is not a defined criterion in the PTEN VCEP v3.2 or in ACMG/AMP 2015; no rule applies.	cspec
PM1	Not met	The frameshift occurs at Arg234 within the C2 domain; the PTEN VCEP-defined catalytic motifs (WPD loop 90-94, P-loop 123-130, TI-loop 166-168) lie N-terminal to this position and are preserved in the truncated protein. No mutational hotspot is present at this residue.	cspec
PM2	Met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying the PTEN VCEP PM2_Supporting threshold (allele frequency <0.001%).	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 applies to in-frame insertions/deletions or stop-loss/protein-extension variants; this is an out-of-frame (frameshift) deletion that is captured by PVS1.	cspec
PM5	N/A	PM5 requires a missense change at a residue where a different missense change is established pathogenic; this is a frameshift deletion, not a missense substitution.	pm5_candidates
PM6	Not met	No assumed de novo observation for this variant has been reported.
PP1	Not met	No co-segregation data with disease in affected family members are available for this variant.
PP2	N/A	PP2 applies to missense variants in a gene with a low rate of benign missense variation; this is a frameshift deletion.	cspec
PP3	Not met	PP3 (PTEN VCEP) requires REVEL >0.7 for missense variants or SpliceAI/VarSeak splicing concordance for splicing variants. REVEL is not computed for this frameshift, and SpliceAI predicts no splice impact (max delta score 0.027), so no computational evidence of a deleterious effect exists.	spliceai
PP4	N/A	The PTEN VCEP marks PP4 not applicable; phenotype specificity is incorporated into the PS4 specifications.	cspec
PP5	N/A	The PTEN VCEP marks PP5 'Not Applicable for this VCEP', and the variant is absent from ClinVar so there is no reputable-source pathogenic classification to credit.	cspec clinvar
BA1	Not met	The variant is absent from gnomAD, far below the BA1 stand-alone threshold (filtering allele frequency >0.056%).	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD, below the BS1 allele-frequency thresholds.	gnomad_v2 gnomad_v4
BS2	Not met	No observation in the homozygous state in a healthy or PHTS-unaffected individual has been reported.	gnomad_v2 gnomad_v4
BS3	Not met	No functional study demonstrating no damaging effect exists for this variant. The Mighell et al. saturation assay (BS3_Supporting path) is missense-only and does not apply to this frameshift.	vcep_mmc2
BS4	Not met	No lack-of-segregation data in affected family members are available.
BP1	N/A	The PTEN VCEP marks BP1 not applicable (missense variant in a gene where truncating variants cause disease is not applicable to PTEN).	cspec
BP2	Not met	No observation in trans with a pathogenic/likely pathogenic PTEN variant, nor three observations in cis/unknown phase with different pathogenic PTEN variants, has been reported.
BP3	N/A	The PTEN VCEP marks BP3 not applicable (in-frame indels in a repetitive region without known function).	cspec
BP4	N/A	BP4 (PTEN VCEP) applies to synonymous or intronic variants with no predicted splicing impact; it is not applicable to a frameshift deletion.	cspec
BP5	Not met	No case with an alternate molecular basis for disease has been reported for this variant.
BP6	N/A	The PTEN VCEP marks BP6 'Not Applicable for this VCEP', and the variant is absent from ClinVar so there is no reputable-source benign classification to credit.	cspec clinvar
BP7	N/A	BP7 applies to synonymous or intronic variants with no predicted splicing impact; this is a frameshift deletion.	cspec
PM3	N/A	Recessive-disorder criterion; PTEN hamartoma tumor syndrome is autosomal dominant and the PTEN VCEP marks PM3 not applicable.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.