NM_000314.8:c.70G>A

PTEN · NP_000305.3:p.(Asp24Asn) · NM_000314.8

GRCh37: chr10:89624296 G>A · GRCh38: chr10:87864539 G>A

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PS3_Moderate PM2_Supporting PP2 PP3

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Asp24Asn)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The PTEN c.70G>A (p.Asp24Asn) variant has been observed in somatic cancers in COSMIC (COSV64295411; 8 occurrences) and has been reported in ClinVar, where it is classified as pathogenic by three clinical laboratory submissions.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.

Functional testing in the PTEN saturation mutagenesis phosphatase assay showed a high-confidence damaging result for D24N (Cum_score -1.549791026), which supports a deleterious effect on PTEN function.

Computational evidence supports a deleterious effect for this missense variant based on a REVEL score of 0.753, while SpliceAI predicts no significant splice impact (maximum delta score 0.02).

Final determination: The combination of PS3_Moderate with PM2_Supporting, PP2, and PP3 does not meet PTEN CSPEC criteria-combination thresholds for Likely Pathogenic, Pathogenic, Likely Benign, or Benign; therefore, this variant is classified as a Variant of Uncertain Significance.

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	N/A	PTEN c.70G>A (p.Asp24Asn; p.D24N) is a missense variant. The PTEN-specific PVS1 decision tree applies to null, canonical splice, frameshift, nonsense, and CNV events rather than missense substitutions.	case_summary.json vcep_materials.json vcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n
PS1	Not met	No evidence was identified for a different nucleotide change producing the same PTEN p.Asp24Asn amino acid substitution that has already been established as pathogenic.	vcep_m_m_c_2 clinvar
PS2	Not assessed	No confirmed de novo data were extracted for this variant.	case_summary.json literature_pass.json
PS3	Met	The PTEN saturation mutagenesis phosphatase assay showed D24N with Cum_score -1.549791026 and High_conf true, which meets the PTEN VCEP threshold for PS3_Moderate (Cum_score <= -1.11).	vcep_m_m_c_2 PMID:29706350 case_summary.json
PS4	Not assessed	The variant is present in ClinVar and has been reported in the literature, but the extracted sources do not provide a PTEN-specific proband specificity score or a case-control enrichment analysis sufficient for PS4 strength assignment.	clinvar literature_pass.json case_summary.json
PM1	Not met	PTEN residue Asp24 is outside the PTEN CSPEC-defined catalytic motif residues 90-94, 123-130, and 166-168 required for PM1. A Cancer Hotspots signal alone does not satisfy the PTEN-specific PM1 definition.	case_summary.json clinvar hotspots
PM2	Met	The variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, satisfying the PTEN PM2_Supporting population criterion.	gnomad_v2 gnomad_v4 case_summary.json
PM3	N/A	PM3 is designated not applicable in the PTEN specification.	case_summary.json
PM4	N/A	This is not an in-frame insertion/deletion or stop-loss variant.	case_summary.json
PM5	Not met	Different missense changes at PTEN Asp24 are present in Table S3 and classified as pathogenic, including p.Asp24His, p.Asp24Tyr, and p.Asp24Gly; however, PM5 additionally requires the queried missense change to have a BLOSUM62 score equal to or less than the known variant. The queried D>N substitution has BLOSUM62 score 1, whereas D>H and D>G are -1 and D>Y is -3, so the PTEN PM5 requirement is not satisfied.	vcep_m_m_c_2 clinvar
PM6	Not assessed	No assumed de novo observations were extracted.	case_summary.json literature_pass.json
PP1	Not assessed	No segregation data were extracted for this variant.	literature_pass.json
PP2	Met	This is a missense variant in PTEN, and PP2 is retained as an applicable PTEN missense-gene-level supporting criterion in the PTEN specification.	case_summary.json
PP3	Met	The REVEL score is 0.753, exceeding the PTEN missense PP3 threshold of >0.7. SpliceAI shows no significant splice effect, but PP3 for PTEN missense variants is based on REVEL.	case_summary.json spliceai revel
PP4	N/A	PP4 is designated not applicable in the PTEN specification.	case_summary.json
PP5	N/A	PP5 is designated not applicable in the PTEN specification.	case_summary.json
BA1	Not met	The variant is absent from gnomAD and does not approach the PTEN BA1 threshold.	gnomad_v2 gnomad_v4 case_summary.json
BS1	Not met	The variant is absent from gnomAD and does not meet the PTEN BS1 population frequency thresholds.	gnomad_v2 gnomad_v4 case_summary.json
BS2	Not assessed	No homozygous observations in healthy or PTEN-hamartoma-tumor-syndrome-unaffected individuals were extracted.	case_summary.json
BS3	Not met	Available functional evidence shows reduced PTEN function rather than no damaging effect. The phosphatase assay score is below the PS3_Moderate threshold, so BS3 is not applicable.	vcep_m_m_c_2 PMID:29706350
BS4	Not assessed	No lack-of-segregation data were extracted.	literature_pass.json
BP1	N/A	BP1 is designated not applicable in the PTEN specification.	case_summary.json
BP2	Not assessed	No phase data with another pathogenic/likely pathogenic PTEN variant were extracted.	case_summary.json
BP3	N/A	BP3 is designated not applicable in the PTEN specification.	case_summary.json
BP4	Not met	The REVEL score is 0.753, which is not below the PTEN BP4 missense threshold of <0.5.	revel case_summary.json
BP5	Not assessed	No alternate highly penetrant molecular diagnosis with non-overlapping phenotype was extracted.	case_summary.json
BP6	N/A	BP6 is designated not applicable in the PTEN specification.	case_summary.json
BP7	N/A	This is not a synonymous or qualifying deep intronic variant.	case_summary.json 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.