Variant classification summary

NM_000314.8:c.525delG

PTEN · NP_000305.3:p.(Tyr176IlefsTer7) · NM_000314.8

GRCh37: chr10:89711906 TG>T · GRCh38: chr10:87952149 TG>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.(Tyr176IlefsTer7)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTEN c.525del (p.Tyr176IlefsTer7; p.Y176Ifs*7) variant has not been observed in COSMIC, has been reported in ClinVar as Pathogenic by one clinical laboratory, and is listed in OncoKB as Likely Oncogenic with a likely loss-of-function effect.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2 threshold of 0.00001 (0.001%) and supports PM2 at supporting strength.

3

This deletion causes a frameshift with premature termination at codon 176 and falls 5' of the PTEN-specific p.D375 (c.1121) PVS1 threshold in transcript NM_000314.8, supporting PVS1 as a loss-of-function variant in a gene where loss of function is an established disease mechanism.

4

SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.02, so no separate computational splice criterion is added.

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 frameshift variant, c.525del (p.Tyr176IlefsTer7), is predicted to introduce a premature termination codon well 5' of the PTEN-specific p.D375 (c.1121) threshold in biologically relevant transcript NM_000314.8, which is consistent with loss of function as an established disease mechanism for PTEN; under the PTEN PVS1 decision tree, this supports PVS1 at very strong strength.	cspec vcep_pvs1_decisiontree_pten pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to the same amino acid substitution as a previously established pathogenic variant or an equivalent pathogenic splicing change; this variant is a frameshift and does not meet that rule type.	cspec
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified, so PS2 cannot be applied from the available evidence.	cspec clinvar
PS3	N/A	No PTEN functional assay result specific to this frameshift variant was identified. The indexed PTEN functional dataset used for PS3/BS3 is a missense phosphatase assay resource and does not provide applicable evidence for this deletion.	cspec vcep_mmc2
PS4	Not met	This variant has been reported in ClinVar, but the available evidence does not provide the PTEN-specific proband scoring, case counts, or case-control enrichment required to apply PS4 at any strength.	cspec clinvar
PM1	N/A	PM1 in the PTEN specification is defined for variants in established catalytic motifs at residues 90-94, 123-130, and 166-168. This frameshift occurs at Tyr176, outside those defined motifs, and is more appropriately evaluated under PVS1.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2 threshold of 0.00001 (0.001%) and supports PM2 at supporting strength.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the PTEN specification.	cspec
PM4	N/A	PM4 in the PTEN specification applies to in-frame insertions/deletions and stop-loss variants. This variant is a frameshift, so PM4 does not apply.	cspec
PM5	N/A	PM5 applies to a missense change at a residue where a different pathogenic or likely pathogenic missense change has been established. This variant is a frameshift and does not meet that rule type.	cspec
PM6	Not assessed	No assumed or confirmed de novo occurrence without family history was identified, so PM6 cannot be applied from the available evidence.	cspec clinvar
PP1	Not assessed	No segregation data were identified, so PP1 cannot be applied.	cspec clinvar
PP2	N/A	PP2 is a missense-specific rule, and this variant is a frameshift.	cspec
PP3	N/A	SpliceAI predicts no significant splice impact for this variant (max delta score 0.02), and the PTEN PP3 rule for splicing variants requires concordant splice prediction evidence. Because this is a frameshift variant already evaluated under PVS1 and no concordant splicing evidence was identified, PP3 is not applied.	cspec spliceai
PP4	N/A	PP4 is not applicable in the PTEN specification.	cspec
PP5	N/A	PP5 is not applicable in the PTEN specification.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the PTEN BA1 threshold of 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 therefore does not fall within the PTEN BS1 supporting range of 0.0000043-0.000043 or the strong range of 0.000043-0.00056.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No homozygous observation in a healthy or PTEN hamartoma tumor syndrome-unaffected individual was identified, so BS2 cannot be applied.	cspec gnomad_v2 gnomad_v4
BS3	N/A	No PTEN functional study showing no damaging effect for this frameshift variant was identified. The indexed PTEN functional assay resource applies to missense variants and does not support BS3 for this deletion.	cspec vcep_mmc2
BS4	Not assessed	No lack-of-segregation evidence from one or more families was identified, so BS4 cannot be applied.	cspec clinvar
BP1	N/A	BP1 is not applicable in the PTEN specification.	cspec
BP2	Not assessed	No phase data showing this variant in trans with a pathogenic PTEN variant or repeated cis/phase-unknown observations with pathogenic PTEN variants were identified, so BP2 cannot be applied.	cspec clinvar
BP3	N/A	BP3 is not applicable in the PTEN specification.	cspec
BP4	N/A	SpliceAI predicts no significant splice impact for this variant (max delta score 0.02), but PTEN BP4 for splicing variants requires concordant computational evidence and this frameshift is not otherwise an appropriate BP4 rule type; therefore BP4 is not applied.	cspec spliceai
BP5	Not assessed	No alternate highly penetrant molecular diagnosis with non-overlapping phenotype was identified, so BP5 cannot be applied.	cspec clinvar
BP6	N/A	BP6 is not applicable in the PTEN specification.	cspec
BP7	N/A	BP7 is limited to synonymous or qualifying intronic variants with no predicted splicing effect. 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.