Variant classification summary

NM_000314.8:c.722_723dup

PTEN · NP_000305.3:p.(Glu242LeufsTer15) · NM_000314.8

GRCh37: chr10:89717695 C>CTT · GRCh38: chr10:87957938 C>CTT

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.(Glu242LeufsTer15)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: the p.E242Lfs*15 frameshift is 5' of the PTEN VCEP p.D375 NMD threshold and is predicted to undergo nonsense-mediated decay.

2

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PTEN VCEP population-frequency rule.

Final determination: PTEN Expert Panel Rule20 assigns Likely Pathogenic when one very strong pathogenic criterion and one supporting pathogenic criterion are present; here these are PVS1 very strong and PM2 supporting.

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	Met: the p.E242Lfs*15 frameshift is 5' of the PTEN VCEP p.D375 NMD threshold, so the decision tree assigns full-strength PVS1.	cspec vcep_pvs1_decisiontree_pten
PS1	N/A	Not applicable: c.722_723dup is a frameshift, whereas PTEN PS1 requires a pathogenic same-amino-acid or qualifying splice-site comparison.	cspec
PS2	Not assessed	Not assessed: no documented proband-level parental testing, confirmed maternity and paternity, or absence of family history for c.722_723dup.	cspec
PS3	Not assessed	Not assessed: the governing PTEN assay table covers missense variants and contains no entry for this frameshift, c.722_723dup / p.E242Lfs*15.	cspec vcep_mmc2
PS4	Not assessed	Not assessed: no variant-specific specificity score or qualifying case-control odds ratio, p value, and confidence interval are available for c.722_723dup.	cspec PMID:21194675 PMID:9467011
PM1	Not met	Not met: residue 242 is outside PTEN VCEP critical motifs 90-94, 123-130, and 166-168, and no E242 hotspot was identified.	cspec
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PTEN PM2 absence criterion below 0.00001 allele frequency.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP explicitly designates PM3 as not applicable for this autosomal-dominant disorder.	cspec
PM4	Not met	Not met: p.E242Lfs*15 is a frameshift with premature termination, whereas the PTEN PM4 rule requires an in-frame length change or stop-loss extension.	cspec
PM5	N/A	Not applicable: c.722_723dup is a frameshift, while PTEN PM5 requires a different pathogenic missense change at the same residue.	cspec
PM6	Not assessed	Not assessed: no documented presumed de novo proband observation, parental testing status, or family-history assessment for c.722_723dup.	cspec
PP1	Not assessed	Not assessed: zero informative meioses or exact-variant affected-relative segregation data are documented, below the PTEN VCEP minimum of 3 meioses.	cspec
PP2	N/A	Not applicable: PP2 is missense-specific, but c.722_723dup produces the frameshift p.(Glu242LeufsTer15).	cspec
PP3	N/A	Not applicable: c.722_723dup is a frameshift variant, outside PP3's calibrated missense or intronic/splice-region computational scope.
PP4	N/A	Not applicable: the PTEN Expert Panel framework incorporates phenotype specificity into PS4 and explicitly excludes independent PP4 use.	cspec
PP5	N/A	Not applicable: PP5 is excluded by the PTEN framework, and ClinVar has no exact-variant expert-panel Pathogenic assertion.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the PTEN BA1 threshold of 0.00056 allele frequency.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, below both PTEN BS1 intervals beginning at 0.0000043 allele frequency.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no homozygous observation in a healthy or PHTS-unaffected individual is available to satisfy the PTEN BS2 rule.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific benign functional result was found for the frameshift c.722_723dup / p.E242Lfs*15 in the governing PTEN assay material.	cspec vcep_mmc2
BS4	Not assessed	Not assessed: no tested affected relatives or family-level non-segregation observations are documented for c.722_723dup.	cspec
BP1	N/A	Not applicable: the PTEN VCEP excludes BP1, and this variant is a frameshift rather than a missense change.	cspec
BP2	Not assessed	Not assessed: no paired pathogenic PTEN variant or documented cis/trans/phase observation is available to satisfy the BP2 rule.	cspec
BP3	N/A	Not applicable: the PTEN VCEP marks BP3 as unavailable, and p.E242Lfs*15 is a truncating frameshift rather than an in-frame repeat-region deletion.	cspec
BP4	N/A	Not applicable: c.722_723dup is a frameshift variant, outside BP4's calibrated missense or intronic/splice-region computational scope.
BP5	Not assessed	Not assessed: no two qualifying cases with a highly penetrant alternate diagnosis and non-overlapping PTEN histories are documented.	cspec oncokb
BP6	N/A	Not applicable: BP6 is excluded by the PTEN framework, and ClinVar has no exact-variant expert-panel Benign or Likely benign assertion.	cspec clinvar
BP7	N/A	Not applicable: c.722_723dup is a frameshift variant, not a synonymous variant eligible for BP7.

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.