PS3 (Moderate): saturation-mutagenesis Cum_score of -1.978 exceeds the <=-1.11 threshold, indicating strongly impaired phosphatase function. PM1 (Moderate): residue 128 lies within the PTEN critical catalytic motif (residues 123-130), a statistically significant hotspot. PM2 (Supporting): variant is absent from gnomAD-Canada v1.0 population data. 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. PP2 (Supporting): missense variant in a gene where missense is a common disease mechanism with a low benign missense rate. PP3 (Supporting): REVEL score 0.921 exceeds the PTEN >0.7 threshold. Overall: Likely Pathogenic, meeting Rule 13 of the ClinGen PTEN Expert Panel v3.2 via three moderate pathogenic criteria (PS3, PM1, PM5).
Final classification
Likely Pathogenic
PS3PM1PM2PM5PP2PP3
PTEN
c.383A>C
p.Lys128Thr
missense · exon 5
Gene context
NCBI Gene ↗
OncoKB ↗
PTEN is a tumor suppressor gene that encodes a phosphatase converting the lipid messenger PIP3 back to PIP2 at the cell membrane, thereby restraining the AKT/mTOR signaling pathway that drives cell growth, proliferation, and survival. It is one of the most frequently mutated genes across many types of human cancer, and its loss promotes unchecked cell growth, survival, and genomic instability, partly through impaired DNA repair. Germline loss-of-function variants in PTEN cause Cowden syndrome, an inherited cancer predisposition disorder associated with elevated risk of breast and thyroid cancer.
This variant
PTEN restrains the AKT/mTOR cell-growth pathway, and germline loss of its function causes Cowden syndrome, an inherited predisposition to breast and thyroid cancer. This Likely Pathogenic classification - based on a catalytic-site change that functional assays show abolishes PTEN phosphatase activity - indicates the variant is expected to impair PTEN's tumor-suppressor function and, if germline, confer Cowden-syndrome-related cancer risk.
Likely Pathogenic: Rule 13 of the ClinGen PTEN Expert Panel v3.2 is met by three moderate pathogenic criteria (PS3, PM1, PM5), with PM2, PP2, and PP3 additionally supporting.
Classification rationale
PS3PM1PM2PM5PP2PP3
Likely Pathogenic
PTEN c.383A>C
missense · exon 5
PS3 + PM1 + PM2 + PM5 + PP2 + PP3
→
Likely Pathogenic
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000314.8 · variants mapped to exon structure
PTEN
NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 6 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 6
Strength
Supporting
Moderate
Strong
Very strong
PS3
moderate
Pathogenic
Met (Moderate): measured phosphatase-assay Cum_score is -1.978, exceeding the <=-1.11 Moderate threshold.
The PTEN VCEP specification identifies mmc2.xlsx as applicable to missense PS3/BS3 assessment and specifies PS3_Moderate for Mighell et al. 2018 phosphatase activity with Cum_score <= -1.11.The exact K128T row in Table S2 of mmc2.xlsx reports Cum_score -1.97828658, High_conf=True, and Pass SE Filter; this is below the PTEN-specific PS3_Moderate cutoff.PMID:21828076 directly tested K128T in a heterologous Saccharomyces cerevisiae PTEN reconstitution assay using PIP3 phosphatase activity, GFP-Akt1 localization, and yeast growth rescue readouts, and reported complete loss of PIP3 phosphatase activity.
PM1
moderate
Pathogenic
Met (Moderate): residue 128 falls within the PTEN critical catalytic motif spanning residues 123-130.
The PTEN VCEP Version 3.2 PM1 rule defines critical catalytic motifs at residues 90-94, 123-130, and 166-168 in NP_000305.3.The normalized variant is NP_000305.3:p.(Lys128Thr), placing the altered residue within the VCEP-defined 123-130 catalytic motif.The case evidence reports that PTEN K128 lies in a statistically significant hotspot.
PM2
supporting
review
Pathogenic
Met (Supporting): variant is absent from gnomAD-Canada v1.0, below the PTEN <0.001% supporting threshold.
The PTEN Expert Panel Version 3.2 PM2 rule specifies supporting evidence for absence or allele frequency <0.00001 (0.001%) in gnomAD or another large sequenced population; when multiple alleles are present in a subpopulation, the subpopulation frequency must be <0.00002 (0.002%).The case bundle explicitly reports NM_000314.8:c.383A>C as absent from gnomAD-Canada v1.0.The gnomAD v2.1/v4.1 query timed out, so those datasets cannot independently confirm the result in this assessment.
PM5
moderate
Pathogenic
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).
The PTEN VCEP Version 3.2 PM5 rule requires a different missense change at the same amino-acid residue that is pathogenic or likely pathogenic, plus a target BLOSUM62 score equal to or less than the known variant.The extracted PTEN VCEP Table S3 entry reports NM_000314.6:c.384G>C (p.Lys128Asn) as likely pathogenic, providing the same-residue comparator.The target is p.Lys128Thr and its BLOSUM62 K→T score (-1) is lower than the comparator K→N score (0), satisfying the VCEP relative-score requirement.
PP2
supporting
Pathogenic
Met (Supporting): missense variant in PTEN, where missense changes are a common disease mechanism with a low benign rate.
The normalized consequence is the missense substitution NP_000305.3:p.(Lys128Thr).The governing PTEN VCEP Version 3.2 lists PP2 as applicable at supporting strength for PTEN missense variants because PTEN has a low rate of benign missense variation and missense variation is a common disease mechanism.
PP3
supporting
Pathogenic
Met (Supporting): REVEL score 0.921 exceeds the PTEN >0.7 PP3 supporting threshold.
ClinGen PTEN Expert Panel Specifications v3.2: for missense variants, PP3_Supporting applies at REVEL score >0.7.The local REVEL lookup for NM_000314.8:c.383A>C reports a score of 0.921, exceeding the PTEN Expert Panel PP3 threshold.
Assessed · not applied
· 4 not met · 11 not assessed
Pathogenic
PVS1
Not met: missense variant with no predicted loss of function; SpliceAI maximum delta is only 0.016.
PS1
Not assessed: no previously established pathogenic K128T allele arising from a different nucleotide change was documented.
PS2
Not assessed: no confirmed de novo occurrence with parental confirmation was documented for this variant.
PS4
Not assessed: the only report is a somatic tumor observation, with no PHTS case-control or phenotype-specificity data.
PM4
Not met: missense substitution does not alter PTEN protein length.
PM6
Not assessed: no presumed or confirmed de novo observation in an affected proband is documented.
PP1
Not assessed: no affected relatives or segregating genotypes are documented for this variant.
Benign
BA1
Not assessed: no population allele frequency was available to test the >0.056% BA1 threshold.
BS1
Not assessed: no quantitative population frequency was available to test the BS1 frequency interval.
BS2
Not assessed: no homozygous observation in a healthy or unaffected individual is documented.
BS3
Not met: functional evidence shows a damaging effect, with complete loss of PIP3 phosphatase activity reported.
BS4
Not assessed: no affected family members negative for the variant are documented.
BP2
Not assessed: no phase or co-occurring PTEN variant data establish a trans or cis configuration.
BP4
Not met: REVEL score 0.921 is above the <0.5 BP4 threshold.
BP5
Not assessed: no qualifying alternate molecular diagnosis is documented.
N/A · 7
PM3 · PP4 · PP5 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
v4.1
This variant is absent from gnomAD v4.1.
v2.1
This variant is absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.921. BayesDel score = 0.409026.
Functional
Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV64288485, n = 2 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 1 further PMID triaged but not cited — see Sources & references.
A comprehensive functional analysis of PTEN mutations: implications in tumor- an
Searched
c.383A>CNP_000305.3:p.(K128T)
Found
The paper explicitly tested the PTEN P-loop substitution K128T, corresponding to the specified protein change. In the yeast functional assay, K128T fully abrogated PTEN PIP3 phosphatase activity.
Variant
✓ Names this variant — characterised directly
Applied to
→PS3
moderate
The exact K128T substitution showed complete loss of PTEN PIP3 phosphatase activity in a functional assay.
→PM1
moderate
The paper directly evaluates K128T within the PTEN P-loop and demonstrates loss of phosphatase activity, supporting the functional criticality of the VCEP-defined 123-130 motif.
A group of mutations (H123Y, C124N, A126D, G127N, K128T, G129D, R130A, R130K, T131I and T131L) fully abrogated the PIP3 phosphatase activity of PTEN in yeast
Location Results, “Functional analysis of mutations at the PTEN P-loop mimicking PTEN-like proteins,” p. 4134; Figure 3 · Context Heterologous PTEN reconstitution assay in Saccharomyces cerevisiae measuring in vivo PIP3 phosphatase activity, with GFP-Akt1 localization and yeast growth rescue readouts. · full text
Sources & reference links
9Sources
Triaged references · 1 PMID not cited in assessment