NM_000314.8:c.155A>T

PTEN · NP_000305.3:p.(Asp52Val) · NM_000314.8

GRCh37: chr10:89653857 A>T · GRCh38: chr10:87894100 A>T

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PM2 supporting PP2 supporting PP3 supporting BS3 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Asp52Val)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

PP2 (Supporting): missense variant in a gene where missense is a common disease mechanism with a low benign missense rate.

PP3 (Supporting): REVEL 0.95 exceeds the >0.7 threshold.

BS3 (Supporting): measured functional score 0.11 indicates retained phosphatase activity.

Overall: VUS under the PTEN Expert Panel v3.2 combination rule, as no pathogenic or benign criterion reaches the required strength.

Final determination: Under the PTEN VCEP Version 3.2 criteria-combination framework, the combination of three pathogenic supporting criteria (PM2, PP2, PP3) and one benign supporting criterion (BS3) matches no final-classification rule; therefore the variant is classified as VUS.

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	Not met: c.155A>T is a missense substitution, p.(Asp52Val), not a null variant, so PVS1 does not apply.	cspec vcep_pvs1_decisiontree_pten pvs1_variant_assessment
PS1	Not assessed	Not assessed: no established pathogenic variant producing the same amino-acid change p.(Asp52Val) was available for comparison.	clinvar cspec
PS2	Not assessed	Not assessed: no de novo observation with parental testing was documented for this variant.	cspec
PS3	Not met	Not met: measured cumulative functional score 0.11 does not reach the <=-1.11 threshold for damaging phosphatase activity.	cspec vcep_mmc2
PS4	Not assessed	Not assessed: no affected-case series or case-control enrichment data were available.	cspec
PM1	Not met	Not met: Asp52 lies outside the PTEN catalytic domains (residues 90-94, 123-130, and 166-168).	cspec
PM2	Met	Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the <0.001% allele-frequency requirement.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: the PTEN Expert Panel specification explicitly excludes PM3.	cspec
PM4	Not met	Not met: p.(Asp52Val) is a single amino-acid substitution with no protein length change.	cspec
PM5	Not assessed	Not assessed: no pathogenic or likely pathogenic missense change at the same residue (Asp52) was available as a comparator.	pm5_candidates cspec
PM6	Not assessed	Not assessed: no presumed de novo occurrence or phenotype/family-history data were documented.	cspec
PP1	Not assessed	Not assessed: no familial segregation data or informative transmissions were available.	cspec
PP2	Met	Met (supporting): missense variant in PTEN, where missense is a common disease mechanism and benign missense variation is rare.	cspec
PP3	Met	Met (supporting): REVEL score 0.95 exceeds the >0.7 threshold.	cspec revel
PP4	N/A	Not applicable: phenotype specificity is already incorporated under PS4.	cspec
PP5	Not assessed	Not assessed: no ClinVar expert-panel pathogenic or likely pathogenic assertion exists for this exact variant.	clinvar
BA1	Not met	Not met: absent from gnomAD, below the >0.056% filtering allele-frequency threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from gnomAD, with no allele frequency in the 0.00043%-0.056% BS1 range.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no homozygous observations in healthy or unaffected individuals were available.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Met	Met (supporting): measured functional score 0.11 indicates retained phosphatase activity (>0 per Mighell et al. 2018).	cspec vcep_mmc2
BS4	Not assessed	Not assessed: no familial genotype-phenotype comparisons or non-segregation observations were documented.	cspec
BP1	N/A	Not applicable: the PTEN Expert Panel designates BP1 as not applicable.	cspec
BP2	Not assessed	Not assessed: no documented trans or cis observation with a pathogenic or likely pathogenic PTEN variant.	cspec
BP3	N/A	Not applicable: designated not applicable by the PTEN Expert Panel; the variant is a missense substitution, not an indel.	cspec
BP4	Not met	Not met: REVEL 0.95 is above the <0.5 threshold required for BP4.	cspec revel spliceai
BP5	Not assessed	Not assessed: no cases with an alternate molecular diagnosis were available.	cspec
BP6	Not assessed	Not assessed: no ClinVar expert-panel benign or likely benign assertion exists for this exact variant.	clinvar
BP7	N/A	Not applicable: exonic missense variant, not synonymous or intronic beyond +7/-21.	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.