Variant classification summary

NM_000314.8:c.405A>G

PTEN · NP_000305.3:p.(Ile135Met) · NM_000314.8

GRCh37: chr10:89692921 A>G · GRCh38: chr10:87933164 A>G

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Pathogenic

PS3 supporting PM2 supporting PM5 moderate PP2 supporting PP3 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Ile135Met)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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).

2

This variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting per PTEN VCEP).

3

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).

4

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).

5

PTEN has a low rate of benign missense variation and missense variants are a common disease mechanism (PP2_Supporting).

6

REVEL in silico prediction score of 0.903 supports a deleterious effect (PP3_Supporting per PTEN VCEP).

7

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.

8

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).

Final determination: Rule15 in the ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified 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	This is a missense variant (c.405A>G, p.Ile135Met). The PTEN PVS1 decision tree is applicable only to null variants (nonsense, frameshift, canonical splice site, and CNV), not to missense substitutions.
PS1	Not met	No other nucleotide change at codon 135 produces the same I135M amino acid substitution that is established as pathogenic. c.405A>G is the only single-nucleotide change that yields Ile135Met.
PS2	Not met	No de novo observation data are available for this variant. None of the reviewed publications report a de novo occurrence of NM_000314.8:c.405A>G.
PS3	Met	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.	vcep_mmc2
PS4	Not met	No proband count or specificity score data are available for this variant to assess enrichment in affected individuals per PTEN VCEP PS4 rules.
PS5	N/A	PS5 is not a recognized criterion in the ACMG/AMP 2015 framework or the PTEN VCEP specifications.
PM1	Not met	Residue 135 is not within the PTEN VCEP-defined catalytic motif residues (NP_000305.3 positions 90-94, 123-130, 166-168). Although position 135 lies in the phosphatase domain and is identified as a statistically significant hotspot by cancerhotspots.org, the VCEP specification explicitly defines eligible residues and position 135 is outside these ranges.	cspec
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	Met	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.	vcep_mmc2 clinvar
PM6	Not met	No de novo observation data are available for this variant. None of the reviewed publications report a de novo occurrence.
PP1	Not met	No co-segregation data are available for this variant. No family studies with meiotic counts were identified in the reviewed literature.
PP2	Met	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.	cspec
PP3	Met	REVEL score of 0.903 exceeds the PTEN VCEP threshold of >0.7 for missense variants, supporting a deleterious computational prediction.	revel cspec
PP4	N/A	The PTEN VCEP specifies that phenotype specificity has been incorporated into the rule specifications for PS4, rendering PP4 not applicable.	cspec
PP5	N/A	The PTEN VCEP marks PP5 as Not Applicable.	cspec
BA1	Not met	This variant is absent from gnomAD and does not meet the PTEN VCEP BA1 threshold of allele frequency >0.056% (0.00056).	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD and does not meet the PTEN VCEP BS1 threshold of allele frequency 0.0043% to 0.056%.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	No evidence of homozygous observation in a healthy or PHTS-unaffected individual is available.
BS3	Not met	The Mighell et al. 2018 saturation mutagenesis assay reports Cum_score = -0.20 for I135M, which is not >0 and therefore does not qualify for BS3_Supporting per the PTEN VCEP. BS3_Strong is restricted to splicing assays for intronic/synonymous variants, which does not apply to this missense variant.	vcep_mmc2 cspec
BS4	Not met	No segregation data showing lack of segregation in affected family members are available for this variant.
BP1	N/A	The PTEN VCEP marks BP1 as Not Applicable.	cspec
BP2	Not met	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	Not met	REVEL score of 0.903 exceeds the PTEN VCEP BP4_Supporting threshold of <0.5 for missense variants. BayesDel score of 0.46 is also not clearly benign.	revel bayesdel cspec
BP5	Not met	No evidence of this variant occurring in a case with an alternate molecular basis for disease that meets PTEN VCEP criteria.
BP6	N/A	The PTEN VCEP marks BP6 as Not Applicable.	cspec
BP7	N/A	This is a missense variant, not a synonymous or intronic variant. BP7 is not applicable.

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