Variant classification summary

NM_000314.8:c.562T>G

PTEN · NP_000305.3:p.(Tyr188Asp) · NM_000314.8

GRCh37: chr10:89711944 T>G · GRCh38: chr10:87952187 T>G

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PS3 moderate PM2 supporting PP3 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Tyr188Asp)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 moderate supports damaging function: the high-confidence Y188D assay score was -2.31723372.

2

PM2 supporting supports rarity: the variant was absent from gnomAD v2.1 and v4.1.

3

PP3 supporting supports a damaging missense effect: REVEL was 0.896.

Final determination: No ClinGen PTEN VCEP Version 3.2 pathogenic or benign combination rule is satisfied by one moderate and two supporting criteria, so the classification is 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	N/A	Not applicable: c.562T>G is a missense variant, whereas the PTEN PVS1 rule covers null, splice-site, initiation-codon, deletion, and duplication variants.	cspec vcep_pvs1_decisiontree_pten
PS1	Not assessed	Not assessed: no independent established pathogenic comparator producing p.Tyr188Asp was identified for this p.Tyr188Asp variant.	cspec clinvar
PS2	Not assessed	Not assessed: no documented de novo observation, confirmed maternity or paternity, or family-history information is available for this variant.	cspec PMID:23519317 PMID:25190698 PMID:27854360 PMID:28492532
PS3	Met	Met at Moderate: Table S2 high-confidence Y188D phosphatase assay score was -2.31723372, below the VCEP PS3_Moderate threshold of -1.11.	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no variant-specific case-control enrichment or scored proband phenotype data were available for NM_000314.8:c.562T>G.	cspec
PM1	Not met	Not met: p.Tyr188Asp is at residue 188, outside all VCEP-listed catalytic motifs 90-94, 123-130, and 166-168, with no hotspot identified.	cspec
PM2	Met	Met at supporting strength: the variant was absent from gnomAD v2.1 and v4.1, below the VCEP PM2 threshold of 0.00001 (0.001%).	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP explicitly states that PM3 is not applicable to PTEN.	cspec
PM4	N/A	Not applicable: p.Tyr188Asp is a missense substitution with no protein-length change, while PTEN PM4 covers only in-frame indels or protein extensions.	cspec
PM5	Not assessed	Not assessed: no usable pathogenic or likely pathogenic missense comparator at Tyr188 was available for the required BLOSUM62 comparison.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no presumed de novo occurrence, parental-testing status, or family-history information is documented for this variant.	cspec PMID:23519317 PMID:25190698 PMID:27854360 PMID:28492532
PP1	Not assessed	Not assessed: no affected relatives, co-segregation results, family count, or meiosis count are documented for this variant.	cspec PMID:23519317 PMID:25190698 PMID:27854360 PMID:28492532
PP2	Not assessed	Not assessed: VCEP-grounded evidence for PTEN's low benign-missense rate and common missense disease mechanism was not available.	cspec
PP3	Met	Met: the missense REVEL score is 0.896, exceeding the PTEN VCEP PP3 threshold of >0.7.	cspec revel
PP4	N/A	Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 Use 2 and marks PP4 not applicable.	cspec
PP5	N/A	Not applicable: the PTEN VCEP explicitly prohibits use of PP5 under its specification.	cspec
BA1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, rather than exceeding the BA1 threshold of 0.00056 (0.056%).	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 reported the variant absent, with no allele frequency in either BS1 interval starting at 0.0000043.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reported no variant observations and therefore supplied no homozygous healthy or PHTS-unaffected individual for BS2.	cspec gnomad_v2 gnomad_v4
BS3	Not met	Not met: high-confidence Y188D had a -2.31723372 phosphatase score, not the VCEP BS3_Supporting requirement of activity greater than 0.	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no affected-family-member testing or documented non-segregation result is available for this variant.	cspec PMID:23519317 PMID:25190698 PMID:27854360 PMID:28492532
BP1	N/A	Not applicable: the PTEN VCEP explicitly states that BP1 is not applicable to PTEN.	cspec
BP2	Not assessed	Not assessed: no qualifying trans observation or at least three cis/phase-unknown observations with different pathogenic PTEN variants are documented.	cspec
BP3	N/A	Not applicable: the PTEN VCEP explicitly states that BP3 is not applicable to PTEN, and this variant is missense rather than an in-frame indel.	cspec
BP4	Not met	Not met: the missense REVEL score is 0.896, above rather than below the PTEN VCEP BP4 threshold of <0.5.	cspec revel
BP5	Not assessed	Not assessed: no two cases with an alternate highly penetrant molecular diagnosis and non-overlapping PTEN histories were documented.	cspec
BP6	N/A	Not applicable: the PTEN VCEP explicitly prohibits use of BP6 under its specification.	cspec
BP7	N/A	Not applicable: c.562T>G is a missense exonic variant, whereas BP7 covers only synonymous or intronic variants at or beyond +7/-21.	cspec

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