PTEN

Final classification

Likely Pathogenic

PTEN c.405A>G · p.Ile135Met

PTEN

NM_000314.8:c.405A>G (p.Ile135Met) is a missense variant in PTEN exon 5, located in the phosphatase domain adjacent to the catalytic motif (residues 123-130).

Gene

PTEN

Transcript

NM_000314.8

HGVS · transcript:coding

NM_000314.8:c.405A>G

Consequence

N/A

GRCh38

chr10:87933164 A>G

GRCh37

chr10:89692921 A>G

Basis ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 criteria-combination framework: matched Rule15 (1 Pathogenic.Moderate + Pathogenic.Supporting >=4) with applied criteria: PS3 supporting, PM2 supporting, PM5 moderate, PP2 supporting, PP3 supporting; maps to Likely Pathogenic. ▾

ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 criteria-combination framework: matched Rule15 (1 Pathogenic.Moderate + Pathogenic.Supporting >=4) with applied criteria: PS3 supporting, PM2 supporting, PM5 moderate, PP2 supporting, PP3 supporting; maps to Likely Pathogenic.

Classification rationale

PS3PM2PM5PP2PP3 Likely Pathogenic

PTEN c.405A>G

NM_000314.8:c.405A>G (p.Ile135Met) is a missense variant in PTEN exon 5, located in the phosphatase domain adjacent to the catalytic motif (residues 123-130).¹ This variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting per PTEN VCEP).² A different missense change at the same residue, I135V (c.403A>G), is classified as Pathogenic in ClinVar (VariationID 142287), satisfying PM5 at moderate strength with BLOSUM62 score comparison (I->M = 1 <= I->V = 3).³ The Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis functional assay reports a cumulative fitness score of -0.20 for I135M (High_conf=True), indicating mildly abnormal cellular fitness. This qualifies for PS3_Supporting per PTEN VCEP as an abnormal in vitro assay not meeting PS3_Moderate (threshold Cum_score <= -1.11).⁴ PTEN has a low rate of benign missense variation and missense variants are a common disease mechanism (PP2_Supporting).⁵ REVEL in silico prediction score of 0.903 supports a deleterious effect (PP3_Supporting per PTEN VCEP).⁶ The variant is not within the PTEN VCEP-defined catalytic motif residues (90-94, 123-130, 166-168) despite being in a statistically significant hotspot region; PM1 is not met.⁷ Applying the PTEN VCEP combination rules: one moderate criterion (PM5) and four supporting criteria (PS3_Supporting, PM2_Supporting, PP2, PP3) do not satisfy any Pathogenic or Likely Pathogenic rule. The variant is classified as a Variant of Uncertain Significance (VUS).⁸

PS3 + PM2 + PM5 + PP2 + PP3 → Likely Pathogenic

1 cspec ↗vcep_mmc2

2 gnomad_v2 ↗gnomad_v4 ↗

3 vcep_mmc2clinvar ↗

4 vcep_mmc2

5 cspec ↗

6 revelcspec ↗

7 cspec ↗

8 cspec ↗

Gene diagram · NM_000314.8 · variants mapped to exon structure

PTEN NM_000314.8

Fetching transcript structure from UCSC…

Applied criteria · 5 applied · 14 assessed

Applied · 5

Strength Supporting Moderate Strong Very strong

✓

PS3 supporting Pathogenic

Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis functional assay reports a cumulative fitness score (Cum_score) of -0.20 for I135M with High_conf=True, indicating mildly abnormal cellular fitness. This does not meet the PS3_Moderate threshold (Cum_score <= -1.11) but qualifies for PS3_Supporting per the PTEN VCEP specification as an abnormal in vitro cellular assay not reaching PS3_Moderate.

Mighell et al. 2018 saturation mutagenesis: I135M Cum_score = -0.20 (High_conf=True)mildly abnormal cellular fitness

✓

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and v4.1, meeting the PTEN VCEP PM2_Supporting threshold of allele frequency <0.001% (0.00001) in large population databases.

Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes/genomes)

gnomad_v2 ↗gnomad_v4 ↗

✓

PM5 moderate Pathogenic

A different missense change at the same residue, I135V (c.403A>G), is classified as Pathogenic in ClinVar (VariationID 142287). BLOSUM62 score for I->M (1) is less than or equal to I->V (3), satisfying the PTEN VCEP BLOSUM62 requirement.

I135V (c.403A>G) classified as Pathogenic in ClinVar (VariationID 142287)BLOSUM62: I->M = 1 <= I->V = 3

clinvar ↗

✓

PP2 supporting Pathogenic

PTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease, meeting the PTEN VCEP PP2_Supporting specification.

PTEN missense constraint: gene has low rate of benign missense variationmissense variants are a common disease mechanism in PTEN

cspec ↗

✓

PP3 supporting Pathogenic

REVEL score of 0.903 exceeds the PTEN VCEP threshold of >0.7 for missense variants, supporting a deleterious computational prediction.

REVEL score = 0.903 > 0.7

cspec ↗

Assessed · not applied

Pathogenic

PS1 No other nucleotide change at codon 135 produces the same I135M amino acid substitution that is established as pathogenic.

PS2 No de novo observation data are available for this variant.

PS4 No proband count or specificity score data are available for this variant to assess enrichment in affected individuals per PTEN VCEP PS4 rules.

PM1 Residue 135 is not within the PTEN VCEP-defined catalytic motif residues (NP_000305.3 positions 90-94, 123-130, 166-168).

PM6 No de novo observation data are available for this variant.

PP1 No co-segregation data are available for this variant.

Benign

BA1 This variant is absent from gnomAD and does not meet the PTEN VCEP BA1 threshold of allele frequency >0.056% (0.00056).

BS1 This variant is absent from gnomAD and does not meet the PTEN VCEP BS1 threshold of allele frequency 0.0043% to 0.056%.

BS2 No evidence of homozygous observation in a healthy or PHTS-unaffected individual is available.

BS3 The Mighell et al.

BS4 No segregation data showing lack of segregation in affected family members are available for this variant.

BP2 No evidence of observation in trans with a pathogenic or likely pathogenic PTEN variant, nor three or more observations in cis/phase unknown with different P/LP PTEN variants.

BP4 REVEL score of 0.903 exceeds the PTEN VCEP BP4_Supporting threshold of <0.5 for missense variants.

BP5 No evidence of this variant occurring in a case with an alternate molecular basis for disease that meets PTEN VCEP criteria.

N/A · 6 PVS1 · PP4 · PP5 · BP1 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 1737440)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.903. BayesDel score = 0.460524.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.

OncoKB ↗

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; COSV64290722, n = 5 times).

Hotspots

This variant lies in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

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. 7 further PMIDs triaged but not cited — see Sources & References.

PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome.

PMID 10400993 ↗ · Marsh DJ et al. · 1999 Aug CLINVAR · case observation

Searched

c.405A>Gp.Ile135MetI135MIle135MetI135

Found

Reports PTEN mutation spectrum in 43 BRR and BRR/CS overlap families. Identifies I135V (c.403A>G) in a familial BRR case (family Ban7) but does not report NM_000314.8:c.405A>G (p.Ile135Met). The I135V finding at the same residue supports PM5 adjudication as a comparator variant.

Variant

◇ Residue / gene-level — variant not named

Applied to

→PM5 supports · met

Why

I135V identified at same residue; used as comparator for PM5 adjudication. I135M itself was not reported in this paper.

Ban7 BRR familial I135V exon 5

Location Table 1 (PTEN mutations in BRR and BRR/CS overlap patients), family Ban7 · full text

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 PMIDs not cited in assessment

10555148 ↗ Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. CLINVAR

10866302 ↗ Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay. CLINVAR

23335809 ↗ High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. CLINVAR

28758351 ↗ Structure and dimerization of the catalytic domain of the protein phosphatase Cdc14p, a key regulator of mitotic exit in Saccharomyces cerevisiae. CLINVAR

9735393 ↗ Novel mutation of the PTEN gene in an Italian Cowden's disease kindred. CLINVAR

15069681 ↗ Molecular alterations associated with cyclin D1 overexpression in endometrial cancer. CLINVAR

16894538 ↗ Bannayan-Riley-Ruvalcaba syndrome with reactive nodular lymphoid hyperplasia and autism and a PTEN mutation. CLINVAR