Variant classification summary

NM_000314.8:c.922_923insT

PTEN · NP_000305.3:p.(Arg308LeufsTer4) · NM_000314.8

GRCh37: chr10:89720771 C>CT · GRCh38: chr10:87961014 C>CT

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.(Arg308LeufsTer4)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: the c.922_923 frameshift lies before PTEN's NMD cutoff.

2

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.

Final determination: Under Rule20 of the ClinGen PTEN Expert Panel Version 3.2 framework, one Pathogenic Very Strong criterion plus one Pathogenic Supporting criterion yields a Likely Pathogenic classification.

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 at very strong strength: the c.922_923 frameshift is 5' of PTEN's c.1121/p.D375 NMD cutoff in NM_000314.8.	cspec vcep_pvs1_decisiontree_pten
PS1	N/A	Not applicable: this exonic frameshift is neither a same-amino-acid missense change nor a pathogenic splicing-site alternative.	cspec
PS2	Not assessed	Not assessed: No documented proband de novo observation, confirmed maternity and paternity, disease status, or family-history evidence is available.	cspec
PS3	Not assessed	Not assessed: mmc2.xlsx contains no matching variant entry, and no qualifying functional assay result demonstrates a damaging effect for this frameshift.	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no PTEN phenotype-specificity score, proband count, or qualifying case-control result is available.	cspec
PM1	Not met	Not met: residue 308 is outside the VCEP catalytic motifs 90–94, 123–130, and 166–168, with no documented hotspot evidence.	cspec
PM2	Met	Met at supporting strength: the variant was absent from gnomAD v2.1 and v4.1, satisfying the VCEP's <0.00001 (0.001%) population-frequency requirement.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP explicitly marks PM3 as not applicable to PTEN.	cspec
PM4	N/A	Not applicable: the c.922_923 insertion is frameshift, whereas PTEN PM4 names only in-frame length changes, stop-loss variants, and protein extensions.	cspec
PM5	N/A	Not applicable: PM5 requires a missense variant, whereas this variant is a frameshift at c.922_923.	cspec
PM6	Not assessed	Not assessed: No assumed de novo observation with disease status, unconfirmed maternity and paternity, and no family history is documented.	cspec
PP1	Not assessed	Not assessed: No affected-family co-segregation data or meiosis count is documented, so the minimum 3-meiosis threshold cannot be evaluated.	cspec
PP2	N/A	Not applicable: PP2 is restricted to missense variants, while NM_000314.8:c.922_923insT is a frameshift.	cspec
PP3	N/A	Not applicable: the variant is an exonic frameshift, whereas PTEN PP3 covers synonymous or intronic variants and missense variants with REVEL >0.7.	cspec
PP4	N/A	Not applicable: the PTEN VCEP explicitly marks PP4 as not applicable and incorporates phenotype specificity into PS4.	cspec
PP5	N/A	Not applicable: the PTEN VCEP explicitly states that PP5 is not for use.	cspec
BA1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, rather than exceeding the >0.00056 (0.056%) BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, so its frequency did not reach the 0.0000043 (0.00043%) BS1-supporting lower bound.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v2.1 and v4.1 reported no variant observation, so no homozygous healthy or PHTS-unaffected individual was identified.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: mmc2.xlsx contains no matching variant entry, and no qualifying functional study shows no damaging effect on this frameshift’s protein function.	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: No family-level lack-of-segregation observation is documented, so the one-family and two-family thresholds cannot be evaluated.	cspec
BP1	N/A	Not applicable: the PTEN VCEP explicitly marks BP1 as not applicable.	cspec
BP2	Not assessed	Not assessed: no qualifying phase-resolved observation with a pathogenic or likely pathogenic PTEN variant is documented.	cspec
BP3	N/A	Not applicable: the PTEN VCEP explicitly states that BP3 is not applicable to PTEN.	cspec
BP4	N/A	Not applicable: the variant is an exonic frameshift, whereas PTEN BP4 covers synonymous or intronic variants and missense variants with REVEL <0.5.	cspec
BP5	Not assessed	Not assessed: no two qualifying alternate-molecular-basis cases with highly penetrant disease and non-overlapping PTEN histories are documented.	cspec
BP6	N/A	Not applicable: the PTEN VCEP explicitly states that BP6 is not for use.	cspec
BP7	N/A	Not applicable: the variant is an exonic frameshift, whereas PTEN BP7 covers only synonymous or intronic variants at or beyond +7/-21.	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.