Variant classification summary

NM_000314.8:c.956del

PTEN · NP_000305.3:p.(Thr319IlefsTer2) · NM_000314.8

GRCh37: chr10:89720804 AC>A · GRCh38: chr10:87961047 AC>A

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.(Thr319IlefsTer2)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTEN c.956del (p.Thr319IlefsTer2; p.T319Ifs*2) variant has been reported in ClinVar as Pathogenic by one clinical laboratory.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases and meeting the PTEN PM2_Supporting threshold of less than 0.00001 (0.001%).

3

This frameshift is predicted to truncate PTEN at codon 320 in exon 8, and the PTEN-specific PVS1 decision tree assigns PVS1 to truncating variants at or 5' to p.D375 (c.1121) in transcript NM_000314.8.

4

SpliceAI predicts no significant splice effect for this variant (max delta score 0.02), and REVEL and BayesDel are not applicable because this is not a single-nucleotide missense variant.

Final determination: Rule20 in the Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as 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	This variant is a frameshift, NM_000314.8:c.956del, predicted to cause p.(Thr319IlefsTer2) [p.(T319Ifs*2)] and truncate PTEN in exon 8 before the PTEN-specific p.D375 (c.1121) threshold. Under the PTEN-specific PVS1 decision tree, truncating variants at or 5' to this threshold in the biologically relevant transcript are assigned PVS1.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_decisiontree_pten
PS1	N/A	PS1 applies to the same amino acid change as a previously established pathogenic variant. This variant is a frameshift, not a missense or equivalent same-amino-acid substitution.	cspec
PS2	Not assessed	No confirmed de novo observation with maternity and paternity established was identified for this variant.	clinvar cspec
PS3	Not assessed	No PTEN functional study meeting the PTEN Expert Panel PS3 rules was identified for this variant. The available PTEN saturation mutagenesis resource is intended for missense phosphatase activity assessment, and no RNA assay showing an abnormal splicing effect was identified.	cspec vcep_mmc2 spliceai
PS4	Not assessed	This variant has a single ClinVar pathogenic submission, but no counted series of unrelated affected individuals, specificity score, or case-control enrichment data were identified to meet the PTEN PS4 rule.	clinvar cspec
PM1	N/A	PM1 in the PTEN specification is used for variants in defined catalytic motifs and hotspot functional regions. This variant is a frameshift at codon 319 and does not fit the PTEN PM1 missense-domain rule.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2 threshold of less than 0.00001 (0.001%) allele frequency and consistent with rarity in population databases.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the PTEN Expert Panel specification.	cspec
PM4	N/A	PM4 in the PTEN specification applies to in-frame insertions or deletions affecting specified motifs or to stop-loss variants. This variant is a frameshift with a premature termination codon, so PM4 does not apply.	cspec
PM5	N/A	PM5 in the PTEN specification uses classic same-residue missense logic. This variant is a frameshift, and the PM5 candidate review determined that classic missense PM5 is not applicable.	cspec pm5_candidates
PM6	Not assessed	No presumed de novo occurrence without full parental confirmation was identified for this variant.	clinvar cspec
PP1	Not assessed	No segregation data were identified showing this variant tracking with PTEN-related disease in informative relatives.	cspec clinvar
PP2	N/A	PP2 applies to missense variation. This variant is a frameshift.	cspec
PP3	N/A	PP3 in the PTEN specification is used for splicing variants with concordant splice predictors or missense variants with REVEL greater than 0.7. This variant is a frameshift, REVEL and BayesDel were not applicable, and SpliceAI showed no significant splice effect with a max delta score of 0.02.	cspec spliceai
PP4	N/A	PP4 is not applicable in the PTEN Expert Panel specification because phenotype specificity is incorporated into PS4.	cspec
PP5	N/A	PP5 is not applicable in the PTEN Expert Panel specification.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and is therefore below the PTEN BA1 threshold of greater than 0.00056 (0.056%).	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and is therefore below the PTEN BS1 thresholds of 0.0000043 to 0.00056.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No observation of this variant in a healthy or PTEN hamartoma tumor syndrome-unaffected homozygous individual was identified.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established PTEN functional study showing no damaging effect was identified for this variant. The available PTEN saturation mutagenesis resource is intended for missense variants and does not provide benign functional evidence for this frameshift.	cspec vcep_mmc2
BS4	Not assessed	No lack-of-segregation data were identified for this variant in one or more families.	cspec clinvar
BP1	N/A	BP1 is not applicable in the PTEN Expert Panel specification.	cspec
BP2	Not assessed	No data were identified showing this variant in trans with a pathogenic PTEN variant or in cis/phase unknown with qualifying pathogenic PTEN variants.	cspec
BP3	N/A	BP3 is not applicable in the PTEN Expert Panel specification.	cspec
BP4	N/A	BP4 in the PTEN specification is used for synonymous or intronic variants with benign splice predictions or missense variants with REVEL less than 0.5. This variant is a frameshift, and although SpliceAI predicts no significant splice impact with a max delta score of 0.02, that does not make BP4 applicable to a truncating coding deletion.	cspec spliceai
BP5	Not assessed	No alternate molecular diagnosis was identified that would explain the phenotype without overlap with PTEN-related disease.	cspec
BP6	N/A	BP6 is not applicable in the PTEN Expert Panel specification.	cspec
BP7	N/A	BP7 applies to synonymous or qualifying intronic variants with no predicted splice impact. This variant is a coding frameshift deletion, so BP7 does not apply.	cspec spliceai

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.