Variant classification summary

NM_000314.8:c.377C>A

PTEN · NP_000305.3:p.(Ala126Asp) · NM_000314.8

GRCh37: chr10:89692893 C>A · GRCh38: chr10:87933136 C>A

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PS3 supporting PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Ala126Asp)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: A126D fully abrogated PTEN PIP3 phosphatase activity in yeast.

2

PM1 moderate: residue 126 lies within the PTEN catalytic motif at residues 123-130.

3

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.

4

PP3 supporting: REVEL score 0.96 exceeds the PTEN threshold of 0.7.

Final determination: Under the PTEN Expert Panel Version 3.2 combination framework, PM1 moderate plus three supporting criteria does not meet any pathogenic or likely pathogenic rule, and no benign rule is met, 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.377C>A is a missense change (p.Ala126Asp), outside the PTEN PVS1 tree's listed loss-of-function variant classes.	cspec pvs1_variant_assessment vcep_pvs1_decisiontree_pten
PS1	Not assessed	Not assessed: no previously established pathogenic variant with the identical p.Ala126Asp amino-acid change was verified.	clinvar PMID:21828076 PMID:32350270
PS2	Not assessed	Not assessed: no qualifying germline de novo observation with parental testing and no-family-history documentation is available for this variant.	cspec PMID:20300775
PS3	Met	Met at supporting strength: A126D fully abrogated PTEN PIP3 phosphatase activity in yeast, while Mighell Cum_score was -1.027466629 and above the -1.11 moderate cutoff.	cspec vcep_mmc2 PMID:29706350 PMID:21828076
PS4	Not assessed	Not assessed: no qualifying case-control statistics or PTEN phenotype-specificity score is available for this variant.	cspec
PM1	Met	Met at moderate strength: residue 126 falls within the VCEP-defined critical catalytic motif spanning residues 123-130.	cspec PMID:21828076
PM2	Met	Met at Supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the VCEP PM2 requirement of allele frequency below 0.00001 (0.001%).	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP explicitly designates PM3 as not applicable, regardless of available phase or affected-proband observations.	cspec
PM4	N/A	Not applicable: p.Ala126Asp is a missense substitution with no protein-length change, whereas PTEN PM4 requires an in-frame indel or stop-loss variant.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: p.Ala126Val is likely pathogenic, but the required BLOSUM62 comparison for p.Ala126Asp is unavailable.	vcep_mmc2 PMID:29706350
PM6	Not assessed	Not assessed: no presumed de novo germline observation in a patient with disease and no family history is documented.	cspec PMID:20300775
PP1	Not assessed	Not assessed: no affected relatives, pedigree, or informative meiosis count is documented for co-segregation evaluation.	cspec
PP2	Not assessed	Not assessed: VCEP-specific evidence for both low benign missense variation and a common missense disease mechanism is absent.	cspec
PP3	Met	Met: REVEL score 0.96 exceeds the PTEN VCEP PP3 missense threshold of >0.7.	cspec revel
PP4	N/A	Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 rather than permitting PP4.	cspec
PP5	N/A	Not applicable: the PTEN VCEP prohibits use of PP5 under the VCEP Review Committee recommendation.	cspec
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the VCEP BA1 threshold of 0.00056 (0.056%).	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 report no allele, below both VCEP BS1 intervals beginning at 0.0000043 (0.00043%).	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no homozygous healthy or PHTS-unaffected individual is reported, and population absence does not establish the VCEP BS2 requirement.
BS3	Not met	Not met: the high-confidence Mighell A126D Cum_score was -1.027466629, below the VCEP BS3 requirement for phosphatase activity >0.	cspec vcep_mmc2 PMID:29706350 PMID:21828076
BS4	Not assessed	Not assessed: no affected relatives lacking the variant are documented in one or more families.	cspec
BP1	N/A	Not applicable: the PTEN VCEP specification explicitly marks BP1 as not applicable.	cspec
BP2	Not assessed	Not assessed: no qualifying trans observation or at least three cis/phase-unknown observations with different pathogenic PTEN variants is documented.	cspec
BP3	N/A	Not applicable: the PTEN VCEP specification explicitly designates BP3 as not applicable.	cspec
BP4	Not met	Not met: REVEL score 0.96 is above, rather than below, the PTEN VCEP BP4 missense cutoff of <0.5.	cspec revel
BP5	Not assessed	Not assessed: at least two qualifying alternate-molecular-basis cases with highly penetrant disease and no PTEN phenotype overlap are not documented.	cspec
BP6	N/A	Not applicable: the PTEN VCEP prohibits use of BP6 under the VCEP Review Committee recommendation.	cspec
BP7	N/A	Not applicable: c.377C>A is a coding missense variant, not a synonymous or intronic variant at or beyond +7/-21.	cspec

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