Variant classification summary

NM_000314.8:c.127dup

PTEN · NP_000305.3:p.(Glu43GlyfsTer9) · NM_000314.8

GRCh37: chr10:89653828 T>TG · GRCh38: chr10:87894071 T>TG

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.(Glu43GlyfsTer9)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PVS1 (very strong) reflects a PTEN frameshift predicted to undergo nonsense-mediated decay.

2

Likely Pathogenic: PM2 (supporting) reflects absence from the evaluated gnomAD populations.

Final determination: PTEN VCEP Rule20 is satisfied by one pathogenic very strong criterion (PVS1) and one pathogenic supporting criterion (PM2), resulting in 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	Met: Frameshift p.Glu43GlyfsTer9 creates a premature stop before p.D375 in transcript NM_000314.8, meeting the VCEP's full PVS1 path.	cspec vcep_pvs1_decisiontree_pten pvs1_variant_assessment
PS1	N/A	Not applicable: c.127dup causes p.(Glu43GlyfsTer9), a frameshift rather than a same-amino-acid substitution or qualifying splice-site variant.	cspec
PS2	Not assessed	Not assessed: no documented de novo observation, parental maternity/paternity confirmation, or family-history information is available.	cspec
PS3	N/A	Not applicable: the governing PTEN functional table is restricted to missense variants, whereas c.127dup is a frameshift with no matching assay row.	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no study reports PTEN c.127dup in affected and control groups, and no proband specificity scores are available for the VCEP PS4 thresholds.	cspec PMID:21194675 PMID:23519317 PMID:23788249 PMID:25394175 PMID:9467011
PM1	Not met	Not met: the frameshift begins at residue 43, outside all VCEP-approved catalytic motifs 90-94, 123-130, and 166-168.	cspec
PM2	Met	Met, Supporting: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, below the VCEP's <0.00001 (0.001%) PM2 threshold.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP explicitly marks PM3 as Not Applicable.	cspec
PM4	N/A	Not applicable: The variant is a frameshift, whereas PTEN PM4 covers only in-frame indels or stop-loss protein-length changes.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: p.(Glu43GlyfsTer9) is a frameshift, while PM5 requires a missense change at the same amino-acid residue.	cspec
PM6	Not assessed	Not assessed: no presumed or assumed de novo observation, parental-confirmation status, observation count, or family-history result is documented.	cspec
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or family-level co-segregation data are documented.	cspec
PP2	N/A	Not applicable: PP2 requires a missense variant, whereas c.127dup produces the frameshift p.(Glu43GlyfsTer9).	cspec
PP3	N/A	Not applicable: c.127dup is a coding frameshift, whereas PTEN PP3 names only splicing variants and missense variants.	cspec
PP4	N/A	Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 Use 2 rather than permitting independent PP4 application.	cspec
PP5	N/A	Not applicable: the PTEN VCEP explicitly prohibits PP5 use, regardless of available pathogenic reports or ClinVar classifications.	cspec
BA1	Not met	Not met: the variant is 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 is absent from gnomAD v2.1 and v4.1, below the 0.0000043 (0.00043%) lower BS1 Supporting boundary.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports no variant observations, so no confirmed homozygous healthy or PHTS-unaffected individual is available for BS2.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the governing PTEN functional table is restricted to missense variants, and this frameshift has no matching row or benign phosphatase result.	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no affected relative without the variant and no documented non-segregation in one or more families are available.	cspec
BP1	N/A	Not applicable: the PTEN VCEP explicitly states that BP1 is not applicable to PTEN.	cspec
BP2	Not assessed	Not assessed: no documented trans observation or three qualifying cis/phase-unknown observations with different pathogenic PTEN variants are available.	cspec
BP3	N/A	Not applicable: The PTEN VCEP explicitly marks BP3 Not Applicable, and this variant is a coding frameshift rather than an in-frame deletion.	cspec pvs1_variant_assessment
BP4	N/A	Not applicable: the coding frameshift is outside PTEN BP4's named splicing-variant and missense predictor paths.	cspec
BP5	Not assessed	Not assessed: no two cases document an alternate highly penetrant molecular diagnosis with personal or family histories excluding overlap with PTEN.	cspec
BP6	N/A	Not applicable: the PTEN VCEP explicitly prohibits BP6 use, regardless of any reputable benign classification source.	cspec
BP7	N/A	Not applicable: c.127dup is an exonic coding frameshift, not a synonymous or intronic variant at or beyond +7/-21.	cspec

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