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 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

Likely Pathogenic: PS3 Moderate is supported by K128T cumulative fitness score -1.97828658 below the PTEN damaging threshold.

2

Likely Pathogenic: PM1 Moderate is supported by Lys128 residing in the critical catalytic interval 123-130.

3

Likely Pathogenic: PM2 Supporting is supported by absence from gnomAD v2.1 and v4.1.

4

Likely Pathogenic: PP2 Supporting applies to this PTEN missense variant under the VCEP missense-disease mechanism rule.

5

Likely Pathogenic: PP3 Supporting is supported by REVEL 0.921 exceeding the PTEN threshold of 0.7.

Final determination: Under Rule14 of the PTEN Expert Panel Version 3.2 framework, two Pathogenic moderate criteria plus at least two Pathogenic supporting criteria classify the variant as Likely Pathogenic.

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.383A>C causes missense p.Lys128Thr, whereas the PTEN PVS1 tree covers null, canonical splice-site, and deletion variants.	cspec
PS1	Not assessed	Not assessed: no established pathogenic comparator with the same Lys128Thr amino-acid change was identified.	cspec clinvar
PS2	Not assessed	Not assessed: no proband-level parental testing, maternity/paternity confirmation, family-history assessment, or germline de novo observation is documented.	cspec
PS3	Met	Met at Moderate: K128T Cum_score -1.97828658 is below the PTEN VCEP PS3 threshold of -1.11 with High_conf=True.	vcep_mmc2 PMID:21828076
PS4	Not assessed	Not assessed: no qualifying PTEN proband specificity score or germline affected-versus-control prevalence estimate is available for this variant.	cspec
PM1	Met	Met at moderate strength: Lys128 lies within the PTEN VCEP critical catalytic-motif interval 123-130.	cspec PMID:21828076
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, below the PTEN PM2 threshold of 0.00001.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: PTEN VCEP 3.2 excludes PM3 because PTEN hamartoma tumor syndrome is autosomal dominant.	cspec
PM4	N/A	Not applicable: p.Lys128Thr is a single-residue missense substitution, not an in-frame length change or stop-loss extension.	cspec
PM5	Not assessed	Not assessed: no pathogenic or likely pathogenic different missense comparator at Lys128 was available for the required BLOSUM62 comparison.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no germline proband-level presumed de novo observation, parental testing, family-history assessment, or phenotype-specific proband documentation is available.	cspec
PP1	Not assessed	Not assessed: no affected relatives, pedigree genotypes, or countable meioses are documented for the variant.	cspec
PP2	Met	Met at supporting strength: the PTEN VCEP explicitly applies PP2 to missense variants in PTEN under its specified missense-disease mechanism rule.	cspec
PP3	Met	Met: missense REVEL score 0.921 exceeds the PTEN VCEP PP3 supporting threshold of >0.7.	cspec revel
PP4	N/A	Not applicable: the PTEN Expert Panel incorporates phenotype specificity into PS4 rather than allowing independent PP4 use.	cspec
PP5	N/A	Not applicable: PTEN PP5 is VCEP-excluded and this exact variant has no ClinVar expert-panel Pathogenic or Likely pathogenic classification.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the PTEN BA1 threshold of 0.00056.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, below both PTEN BS1 frequency ranges beginning at 0.0000043.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no homozygous observation or parental confirmation is available, while gnomAD v2.1 and v4.1 report the variant absent.	cspec gnomad_v2 gnomad_v4
BS3	Not met	Not met: K128T Cum_score -1.97828658 is not greater than the PTEN VCEP BS3 threshold of 0 and indicates loss of function.	vcep_mmc2 PMID:21828076
BS4	Not assessed	Not assessed: no affected non-carriers, family genotypes, pedigree data, or documented non-segregation observations are available.	cspec
BP1	N/A	Not applicable: the governing PTEN VCEP explicitly excludes BP1.	cspec
BP2	Not assessed	Not assessed: no affected-proband phase data or qualifying observations with another pathogenic or likely pathogenic PTEN variant are documented.	cspec
BP3	N/A	Not applicable: the PTEN VCEP explicitly marks BP3 as Not Applicable, and this variant is missense rather than a repeat-region in-frame indel.	cspec
BP4	Not met	Not met: missense REVEL score 0.921 is above the PTEN VCEP BP4 supporting threshold of <0.5.	cspec revel
BP5	Not assessed	Not assessed: an acquired MITF amplification in a melanoma cohort does not establish the PTEN VCEP's required highly penetrant alternate germline disease and non-overlapping history.	cspec PMID:24265153
BP6	N/A	Not applicable: PTEN BP6 is VCEP-excluded and this exact variant has no ClinVar expert-panel Benign or Likely benign classification.	cspec clinvar
BP7	N/A	Not applicable: c.383A>C produces missense p.Lys128Thr, not a synonymous or qualifying intronic variant.

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