Variant classification summary

NM_000314.8:c.357dup

PTEN · NP_000305.3:p.(Ala120CysfsTer6) · NM_000314.8

GRCh37: chr10:89692871 G>GT · GRCh38: chr10:87933114 G>GT

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.(Ala120CysfsTer6)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: the early c.357 frameshift is 5' of the PTEN VCEP's c.1121 p.D375 NMD threshold.

2

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

Final determination: PTEN VCEP Rule20 classifies a variant as 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: Full-strength PVS1 applies because the c.357 frameshift is 5' of the VCEP's c.1121 p.D375 NMD threshold in NM_000314.8.	cspec vcep_pvs1_decisiontree_pten
PS1	N/A	Not applicable: the queried variant is a frameshift, p.(Ala120CysfsTer6), not a missense change with a comparable amino-acid substitution.	cspec
PS2	Not assessed	Not assessed: no proband-level de novo observation, parental testing, maternity/paternity confirmation, or family-history information is documented.	cspec
PS3	Not assessed	Not assessed: mmc2.xlsx has no c.357dup or p.A120Cfs*6 entry, so the VCEP's <= -1.11 phosphatase-score rule cannot be evaluated.	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no case-control odds ratio, confidence interval, or phenotype-specificity score is available to compare with the PTEN PS4 thresholds.
PM1	Not met	Not met: the frameshift starts at codon 120, outside the VCEP catalytic-motif intervals 90-94, 123-130, and 166-168.	cspec pm5_candidates
PM2	Met	Met at Supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PTEN VCEP requirement for frequency below 0.00001 (0.001%).	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP explicitly designates PM3 as not applicable.	cspec
PM4	N/A	Not applicable: The variant is a premature-termination frameshift, whereas the VCEP PM4 rule is limited to in-frame length changes, stop-loss, and protein extensions.	cspec
PM5	N/A	Not applicable: PM5 requires a missense change, whereas c.357dup is a frameshift producing p.(Ala120CysfsTer6).	cspec pm5_candidates
PM6	Not assessed	Not assessed: no presumed de novo observation, affected proband documentation, family-history assessment, or parental-confirmation data is available.	cspec
PP1	Not assessed	Not assessed: no affected relatives, segregation results, family structure, or countable meioses are documented for c.357dup.	cspec
PP2	N/A	Not applicable: PP2 is limited to missense variants, while c.357dup is a frameshift producing p.(Ala120CysfsTer6).	cspec
PP3	N/A	Not applicable: c.357dup is a coding frameshift, outside PP3's synonymous/intronic splice-prediction and missense REVEL scopes.	cspec
PP4	N/A	Not applicable: the PTEN VCEP directs phenotype-specific evidence to PS4 Use 2 rather than applying PP4.	cspec
PP5	N/A	Not applicable: the PTEN VCEP explicitly prohibits use of PP5 under its governing specification.	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, so its observed frequency is not within either 0.0000043–0.00056 BS1 interval.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: no homozygous healthy or PHTS-unaffected individual is reported, whereas the VCEP requires one confirmed or two unconfirmed observations.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: mmc2.xlsx has no exact frameshift entry, so the VCEP's >0 phosphatase-activity rule cannot establish benign functional evidence.	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no affected relatives or family-level lack-of-segregation observation is documented for c.357dup.	cspec
BP1	N/A	Not applicable: the PTEN VCEP explicitly marks BP1 as Not Applicable.	cspec
BP2	Not assessed	Not assessed: no cis, trans, or phase data, and no qualifying pathogenic/likely pathogenic PTEN partner observation is documented.	cspec clinvar
BP3	N/A	Not applicable: The PTEN VCEP explicitly marks BP3 as Not Applicable for this framework.	cspec
BP4	N/A	Not applicable: c.357dup is a coding frameshift, outside BP4's synonymous/intronic splice-prediction and missense REVEL scopes.	cspec
BP5	Not assessed	Not assessed: no two qualifying cases with a highly penetrant alternate diagnosis and non-overlapping PTEN histories are documented.
BP6	N/A	Not applicable: the PTEN VCEP explicitly prohibits use of BP6 under its governing specification.	cspec
BP7	N/A	Not applicable: c.357dup is a coding frameshift, whereas BP7 is limited to 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.