Variant classification summary

NM_000314.8:c.775_781del

PTEN · NP_000305.3:p.(His259ArgfsTer5) · NM_000314.8

GRCh37: chr10:89717748 TCCACAAA>T · GRCh38: chr10:87957991 TCCACAAA>T

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.(His259ArgfsTer5)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): frameshift p.(His259ArgfsTer5) truncates upstream of the PTEN NMD cutoff at c.1121, predicting nonsense-mediated decay.

2

PM2 (Supporting): variant is absent from gnomAD v2.1 and v4.1, below the 0.001% allele-frequency threshold.

3

Combined, PVS1 plus PM2 matches ClinGen PTEN VCEP Rule 20, supporting a classification of Likely Pathogenic.

Final determination: PTEN VCEP v3.2 Rule20: PVS1 (Very Strong) plus one Supporting-level criterion (PM2_Supporting) combine to 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 (Very Strong): frameshift p.(His259ArgfsTer5) truncates well before the PTEN VCEP NMD cutoff at c.1121, predicting nonsense-mediated decay.	cspec vcep_pvs1_decisiontree_pten pvs1_gene_context pvs1_variant_assessment
PS1	N/A	Not applicable: PS1 applies only to missense variants, and this is a 7-bp frameshift deletion with no single amino-acid change.	cspec
PS2	Not assessed	Not assessed: no parental test results or parentage confirmation were available to establish a confirmed de novo occurrence.	cspec
PS3	Not assessed	Not assessed: VCEP functional-evidence rules cover only missense (Mighell assay) or splice variants, and no variant-specific functional study of this frameshift was available.
PS4	Not assessed	Not assessed: no affected-case observations or case-control enrichment data for this exact variant were available.	cspec
PM1	N/A	Not applicable: PM1 covers missense or in-frame indels in catalytic motifs (residues 90-94, 123-130, 166-168); this frameshift falls outside them.	cspec
PM2	Met	Met (Supporting): absent from gnomAD v2.1 and v4.1, below the PTEN 0.001% allele-frequency threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: the PTEN Expert Panel designates PM3 not applicable because PTEN hamartoma tumor syndrome is autosomal dominant.	cspec
PM4	N/A	Not applicable: PM4 requires an in-frame length change or stop-loss; this deletion shifts the reading frame (p.His259ArgfsTer5).	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: PM5 compares missense substitutions at the same residue; this frameshift produces no single amino-acid change.	cspec
PM6	Not assessed	Not assessed: no parental testing or family-history data were available to document a presumed de novo occurrence.	cspec
PP1	Not assessed	Not assessed: no pedigree or affected-relative genotype data were available to evaluate co-segregation.	cspec
PP2	N/A	Not applicable: PP2 applies to missense variants, and this is a frameshift deletion.	cspec
PP3	N/A	Not applicable: VCEP PP3 covers only missense (REVEL) and splice variants; this frameshift is neither, and SpliceAI max delta is 0.037.	cspec spliceai
PP4	N/A	Not applicable: the PTEN Expert Panel folds phenotype specificity into PS4, so PP4 is not used.	cspec
PP5	Not met	Not met: the exact variant is absent from ClinVar, so no expert-panel pathogenic assertion exists to support PP5.	clinvar
BA1	Not met	Not met: absent from gnomAD v2.1 and v4.1, far below the PTEN BA1 threshold of >0.056% allele frequency.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: absent from gnomAD v2.1 and v4.1, below the PTEN BS1 frequency ranges.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no homozygous observations were available to evaluate presence in healthy individuals.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: VCEP BS3 rules (Mighell missense assay, splice assays) do not cover frameshifts, and no variant-specific benign functional study was available.
BS4	Not assessed	Not assessed: no variant-negative affected relatives were documented, so non-segregation could not be evaluated.	cspec
BP1	N/A	Not applicable: the PTEN VCEP marks BP1 not applicable, and this is a frameshift, not a missense variant.	cspec
BP2	Not assessed	Not assessed: no second pathogenic PTEN variant or phase data were available to evaluate.	cspec
BP3	N/A	Not applicable: the PTEN VCEP marks BP3 not applicable, and this is a frameshift, not an in-frame indel.	cspec
BP4	N/A	Not applicable: VCEP BP4 covers only missense and splice variants; this frameshift deletion is neither.	cspec spliceai
BP5	Not assessed	Not assessed: no data documented an alternate molecular diagnosis explaining the phenotype.	cspec
BP6	Not met	Not met: the exact variant is absent from ClinVar, so no expert-panel benign assertion exists to support BP6.	clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or deep-intronic variants, and this is a coding frameshift deletion.	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.