Variant classification summary

NM_000314.8:c.383A>C

PTEN · NP_000305.3:p.(Lys128Thr) · NM_000314.8

GRCh37: chr10:89692899 A>C · GRCh38: chr10:87933142 A>C

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Pathogenic

PS3 moderate PM1 moderate PM5 moderate PM2 supporting PP2 supporting PP3 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Lys128Thr)

gnomAD AF

ClinVar

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 (Moderate): saturation-mutagenesis Cum_score of -1.978 exceeds the <=-1.11 threshold, indicating strongly impaired phosphatase function.

2

PM1 (Moderate): residue 128 lies within the PTEN critical catalytic motif (residues 123-130), a statistically significant hotspot.

3

PM2 (Supporting): variant is absent from gnomAD-Canada v1.0 population data.

4

PM5 (Moderate): a different pathogenic missense change at the same residue (p.Lys128Asn) is documented, with a BLOSUM62 score no more favorable than the target change.

5

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

6

PP3 (Supporting): REVEL score 0.921 exceeds the PTEN >0.7 threshold.

7

Overall: Likely Pathogenic, meeting Rule 13 of the ClinGen PTEN Expert Panel v3.2 via three moderate pathogenic criteria (PS3, PM1, PM5).

Final determination: PTEN VCEP Rule13 classifies a variant as Likely Pathogenic when three or more moderate pathogenic criteria are met.

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: missense variant with no predicted loss of function; SpliceAI maximum delta is only 0.016.	cspec vcep_pvs1_decisiontree_pten pvs1_variant_assessment spliceai
PS1	Not assessed	Not assessed: no previously established pathogenic K128T allele arising from a different nucleotide change was documented.	cspec PMID:24265153 vcep_mmc2
PS2	Not assessed	Not assessed: no confirmed de novo occurrence with parental confirmation was documented for this variant.	cspec
PS3	Met	Met (Moderate): measured phosphatase-assay Cum_score is -1.978, exceeding the <=-1.11 Moderate threshold.	cspec vcep_mmc2 PMID:21828076
PS4	Not assessed	Not assessed: the only report is a somatic tumor observation, with no PHTS case-control or phenotype-specificity data.	cspec PMID:24265153
PM1	Met	Met (Moderate): residue 128 falls within the PTEN critical catalytic motif spanning residues 123-130.	cspec PMID:21828076
PM2	Met	Met (Supporting): variant is absent from gnomAD-Canada v1.0, below the PTEN <0.001% supporting threshold.	cspec gnomad_canada gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN Expert Panel excludes PM3 because PTEN hamartoma tumor syndrome is autosomal dominant.	cspec
PM4	Not met	Not met: missense substitution does not alter PTEN protein length.	cspec pvs1_variant_assessment
PM5	Met	Met (Moderate): a pathogenic change at the same residue (K128N) exists, and its BLOSUM62 score K->T (-1) is no higher than comparator K->N (0).	cspec vcep_mmc2
PM6	Not assessed	Not assessed: no presumed or confirmed de novo observation in an affected proband is documented.	cspec
PP1	Not assessed	Not assessed: no affected relatives or segregating genotypes are documented for this variant.	cspec
PP2	Met	Met (Supporting): missense variant in PTEN, where missense changes are a common disease mechanism with a low benign rate.	cspec
PP3	Met	Met (Supporting): REVEL score 0.921 exceeds the PTEN >0.7 PP3 supporting threshold.	cspec revel
PP4	N/A	Not applicable: phenotype specificity is already captured under PS4 in the PTEN framework.	cspec
PP5	N/A	Not applicable: the PTEN Expert Panel does not use PP5, and the variant is absent from ClinVar.	cspec clinvar
BA1	Not assessed	Not assessed: no population allele frequency was available to test the >0.056% BA1 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not assessed	Not assessed: no quantitative population frequency was available to test the BS1 frequency interval.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no homozygous observation in a healthy or unaffected individual is documented.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not met	Not met: functional evidence shows a damaging effect, with complete loss of PIP3 phosphatase activity reported.	cspec vcep_mmc2 PMID:21828076
BS4	Not assessed	Not assessed: no affected family members negative for the variant are documented.	cspec
BP1	N/A	Not applicable: the PTEN Expert Panel Version 3.2 designates BP1 unused.	cspec
BP2	Not assessed	Not assessed: no phase or co-occurring PTEN variant data establish a trans or cis configuration.	cspec
BP3	N/A	Not applicable: the PTEN Expert Panel does not use BP3, and this is a missense change, not an in-frame indel.	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL score 0.921 is above the <0.5 BP4 threshold.	cspec revel
BP5	Not assessed	Not assessed: no qualifying alternate molecular diagnosis is documented.	cspec PMID:24265153
BP6	N/A	Not applicable: the PTEN Expert Panel does not use BP6, and the variant is absent from ClinVar.	cspec clinvar
BP7	N/A	Not applicable: BP7 is limited to synonymous or intronic variants, and this is a missense change.	cspec

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