Variant classification summary

NM_000314.8:c.263A>G

PTEN · NP_000305.3:p.(Tyr88Cys) · NM_000314.8

GRCh37: chr10:89692779 A>G · GRCh38: chr10:87933022 A>G

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PS3 moderate PM2 supporting PP2 supporting PP3 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Tyr88Cys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTEN c.263A>G (p.Tyr88Cys; p.Y88C) variant has been observed in somatic cancers in COSMIC (11 occurrences) and has not been reported in ClinVar.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in the general population and meeting the PTEN Expert Panel PM2_Supporting threshold.

3

In a published PTEN multiplex phosphatase assay, p.Tyr88Cys had a cumulative functional score of -1.228, which is below the PTEN Expert Panel PS3_Moderate threshold of -1.11 and supports a damaging effect on PTEN function.

4

Computational evidence supports a deleterious effect, with REVEL 0.927 above the PTEN Expert Panel PP3 threshold of 0.7 and BayesDel 0.567202, while SpliceAI predicts no meaningful splice impact with a maximum delta score of 0.03.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v3.2.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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	Not met	This missense variant does not fall into the PTEN PVS1 null-variant categories. Available PTEN-specific and generic PVS1 guidance indicates that c.263A>G (p.Tyr88Cys) is not a nonsense, frameshift, or canonical splice-site variant, so PVS1 is not applied.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_decisiontree_pten
PS1	Not met	No previously established pathogenic PTEN variant producing the same amino acid change was identified. Available ClinVar evidence does not support PS1 for p.Tyr88Cys.	clinvar cspec
PS2	Not assessed	No confirmed de novo observation with maternity and paternity testing was identified, so PS2 cannot be assessed from the available evidence.	clinvar cspec
PS3	Met	In a published PTEN multiplex phosphatase assay, p.Tyr88Cys showed a cumulative functional score of -1.228, which is below the PTEN Expert Panel PS3_Moderate threshold of -1.11. This supports a damaging effect on PTEN function.	vcep_mmc2 cspec
PS4	Not assessed	This variant has been observed in somatic cancers, but no germline case-count, specificity-score, or case-control evidence was identified to support PS4 under the PTEN Expert Panel rules.	clinvar cspec
PM1	Not met	p.Tyr88Cys is not within the PTEN catalytic motif residues defined by the Expert Panel for PM1 (residues 90-94, 123-130, and 166-168), and no statistically significant hotspot was identified from the available review. Available evidence does not support PM1.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. Its observed population frequency is therefore below the PTEN Expert Panel PM2_Supporting threshold of 0.001% and supports rarity in the general population.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable under the PTEN Expert Panel framework.	cspec
PM4	N/A	PM4 is intended for in-frame insertions or deletions and stop-loss variants. This variant is a missense substitution, so PM4 is not applicable.	cspec
PM5	Not met	No different missense change at PTEN Tyr88 established as pathogenic or likely pathogenic was identified in the available ClinVar review. Available evidence does not support PM5.	clinvar cspec
PM6	Not assessed	No assumed de novo observation without confirmed parentage was identified, so PM6 cannot be assessed from the available evidence.	clinvar cspec
PP1	Not assessed	No informative segregation data were identified for this variant, so PP1 cannot be assessed.	clinvar cspec
PP2	Met	This is a missense variant in PTEN, a gene for which the PTEN Expert Panel permits PP2 because benign missense variation is relatively low and missense variants are a recognized disease mechanism. This supports PP2 at supporting strength.	cspec
PP3	Met	Computational evidence supports a deleterious effect. REVEL is 0.927, which is above the PTEN Expert Panel PP3 threshold of 0.7 for missense variants; BayesDel is also in a deleterious range at 0.567202. SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.03, supporting a protein-impact rather than splice-impact interpretation.	cspec revel bayesdel spliceai
PP4	N/A	PP4 is not applicable under the PTEN Expert Panel framework because phenotype specificity is incorporated into PS4 scoring.	cspec
PP5	N/A	PP5 is not applicable under the PTEN Expert Panel framework.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its frequency is below the PTEN Expert Panel BA1 threshold of 0.056%. BA1 is not met.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its frequency is below the PTEN Expert Panel BS1 thresholds of 0.00043% for supporting and 0.0043% for strong evidence. BS1 is not met.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	No homozygous observation in a healthy or PTEN hamartoma tumor syndrome-unaffected individual was identified. Available evidence does not support BS2.	gnomad_v2 gnomad_v4 cspec
BS3	Not met	Available functional evidence does not show retained PTEN function. In the published multiplex phosphatase assay, p.Tyr88Cys had a damaging score of -1.228 rather than a score above 0 required for BS3_Supporting, so BS3 is not met.	vcep_mmc2 cspec
BS4	Not assessed	No family study demonstrating lack of segregation was identified, so BS4 cannot be assessed from the available evidence.	clinvar cspec
BP1	N/A	BP1 is not applicable under the PTEN Expert Panel framework.	cspec
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic PTEN variant or in cis/phase unknown with the number of pathogenic variants required by the PTEN Expert Panel. BP2 cannot be assessed.	clinvar cspec
BP3	N/A	BP3 is not applicable under the PTEN Expert Panel framework.	cspec
BP4	Not met	Computational evidence does not support a benign interpretation. REVEL is 0.927, which is above rather than below the PTEN Expert Panel BP4 missense threshold of 0.5. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, the missense prediction profile does not support BP4.	cspec revel spliceai
BP5	Not assessed	No alternate highly penetrant molecular explanation with non-overlapping clinical features was identified, so BP5 cannot be assessed from the available evidence.	cspec
BP6	N/A	BP6 is not applicable under the PTEN Expert Panel framework.	cspec
BP7	N/A	BP7 applies to synonymous or qualifying intronic variants without predicted splice impact. This variant is missense, so BP7 is not applicable.	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.