NM_000314.8:c.955_956dup

PTEN · NP_000305.3:p.(Thr321Ter) · NM_000314.8

GRCh37: chr10:89720803 T>TAC · GRCh38: chr10:87961046 T>TAC

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Pathogenic

PVS1 PM2_Supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Thr321Ter)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The PTEN c.955_956dup (p.Thr321Ter; p.T321*) variant has not been observed in somatic cancers in COSMIC, has not been reported in ClinVar, and is listed by OncoKB as Likely Oncogenic with a likely loss-of-function effect.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PTEN PM2 at Supporting strength.

PTEN-specific null-variant guidance supports PVS1 at Very Strong strength because this duplication introduces a premature termination codon at p.Thr321, which is upstream of the PTEN p.D375 (c.1121) NMD cutoff in transcript NM_000314.8.

SpliceAI predicts no significant splice effect for NM_000314.8:c.955_956dup (max delta score 0.01), and the residue is outside the PTEN PM1 catalytic motifs with no Cancer Hotspots signal at T321.

Final determination: Likely Pathogenic based on 1 Very Strong criterion (PVS1) plus 1 Supporting criterion (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	Using the PTEN-specific PVS1 decision tree, NM_000314.8:c.955_956dup is a null variant that introduces a premature termination codon at p.(Thr321Ter), which is 5' of the PTEN NMD cutoff at p.D375 (c.1121); this supports PVS1 at Very Strong strength.	cspec vcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n
PS1	Not assessed	No prior pathogenic variant with the same amino acid change or qualifying same-nucleotide pathogenic splice comparator was documented in the reviewed workspace.	cspec clinvar
PS2	Not assessed	No confirmed de novo observation with maternity and paternity confirmation was present in the workspace.	cspec
PS3	Not assessed	No variant-specific functional study meeting PTEN PS3 rules was identified. The indexed Mighell assay file is designated for missense variants, and no RNA/minigene splicing assay for this duplication was provided.	cspec vcep_m_m_c_2
PS4	Not assessed	No proband-count, phenotype-specificity score, or case-control enrichment data sufficient for PTEN PS4 were assembled in the workspace.	cspec clinvar cosmic
PM1	Not met	PTEN PM1 is restricted to catalytic motif residues 90-94, 123-130, and 166-168. The observed stop at residue 321 lies outside these motifs, and Cancer Hotspots found no significant hotspot at T321.	cspec hotspots
PM2	Met	The variant is absent from both gnomAD v2.1 and gnomAD v4.1, satisfying the PTEN PM2_Supporting rule for an ultra-rare or absent allele in population databases.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable for PTEN per the VCEP specification.	cspec
PM4	N/A	PTEN PM4 applies to in-frame insertions/deletions affecting defined regions or to stop-loss/protein-extension variants. This variant introduces a premature stop codon rather than an in-frame length change or stop-loss.	cspec
PM5	N/A	PM5 is a missense-residue criterion and does not apply to a truncating variant.	cspec
PM6	Not assessed	No assumed de novo observation without parental confirmation was documented in the workspace.	cspec
PP1	Not assessed	No segregation data across informative meioses were provided for PP1 assessment.	cspec
PP2	N/A	PP2 is a missense criterion and does not apply to this truncating variant.	cspec
PP3	Not assessed	PTEN PP3 requires concordant splicing predictors for qualifying splicing variants or REVEL >0.7 for missense variants. This workspace only showed SpliceAI with no significant splice impact and no qualifying VarSeak/REVEL evidence for PP3 application.	cspec spliceai
PP4	N/A	PP4 is marked not applicable by the PTEN VCEP because phenotype specificity is incorporated into PS4 usage.	cspec
PP5	N/A	PP5 is not for use in this VCEP framework.	cspec
BA1	Not met	The variant is absent from gnomAD and therefore does not meet the PTEN BA1 population threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD and does not reach the PTEN BS1 supporting or strong frequency ranges.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No homozygous observations in healthy or PTEN-hamartoma-spectrum-unaffected individuals were provided.	cspec
BS3	Not assessed	No variant-specific functional evidence showing no damaging effect was identified. The indexed Mighell assay is for missense variants, and no no-effect RNA/splicing assay for this duplication was provided.	cspec vcep_m_m_c_2
BS4	Not assessed	No segregation dataset demonstrating lack of segregation in one or more families was present.	cspec
BP1	N/A	BP1 is marked not applicable by the PTEN VCEP.	cspec
BP2	Not assessed	No phase data or observations with other pathogenic/likely pathogenic PTEN variants were assembled for BP2 assessment.	cspec
BP3	N/A	BP3 is not applicable to PTEN per the VCEP specification.	cspec
BP4	Not assessed	PTEN BP4 requires concordant benign splicing prediction for qualifying splicing variants or REVEL <0.5 for missense variants. The workspace only provides SpliceAI and no VarSeak result, and the variant is not a missense substitution.	cspec spliceai
BP5	Not assessed	No evidence of an alternate highly penetrant molecular diagnosis with non-overlapping phenotype was assembled.	cspec
BP6	N/A	BP6 is not for use in this VCEP framework.	cspec
BP7	N/A	BP7 is limited to synonymous or qualifying intronic variants and does not apply to this truncating exonic duplication.	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.