Variant classification summary

NM_000314.8:c.1082G>T

PTEN · NP_000305.3:p.(Ser361Ile) · NM_000314.8

GRCh37: chr10:89725099 G>T · GRCh38: chr10:87965342 G>T

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Benign

PM2 supporting PP2 supporting BS3 supporting BP4 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Ser361Ile)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: BS3 supporting reflects high-confidence positive phosphatase activity with Cum_score 0.154.

2

Likely Benign: BP4 supporting reflects a REVEL score of 0.438, below the VCEP cutoff of 0.5.

3

Not independently classifying: PM2 supporting reflects absence from gnomAD v2.1 and v4.1 but does not satisfy a pathogenic rule alone.

4

Not independently classifying: PP2 supporting applies to this PTEN missense variant but does not satisfy a pathogenic rule alone.

Final determination: Under Rule19 of the ClinGen PTEN Expert Panel Version 3.2 framework, at least two benign supporting criteria are required; BS3 supporting and BP4 supporting satisfy that rule and yield Likely Benign.

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.1082G>T is a missense substitution (p.Ser361Ile), whereas the PTEN PVS1 tree covers loss-of-function variant classes, not missense variants.	cspec vcep_pvs1_decisiontree_pten
PS1	Not met	Not met: p.(Ser361Ile) has only a single-submitter ClinVar uncertain-significance record, with no established pathogenic same-amino-acid variant identified.	cspec clinvar
PS2	Not assessed	Not assessed: no documented de novo observation, parental maternity or paternity confirmation, or family-history assessment is available.	cspec
PS3	Not met	Not met: high-confidence Table S2 phosphatase activity (Cum_score) was 0.154, above the PS3_Moderate cutoff of <= -1.11.	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no variant-specific case-control counts, odds ratio, confidence interval, or qualifying PTEN phenotype-specificity scores are available.	cspec PMID:25394175
PM1	Not met	Not met: residue 361 is outside all VCEP-approved catalytic motifs, which are limited to residues 90-94, 123-130, and 166-168.	cspec hotspots
PM2	Met	Met at Supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the VCEP PM2 requirement of <0.00001 (0.001%) allele frequency.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP explicitly excludes PM3 for PTEN.	cspec
PM4	N/A	Not applicable: p.Ser361Ile is a missense substitution and causes no protein-length change, whereas the PTEN PM4 rule requires in-frame indel or stop-loss length changes.	cspec
PM5	Not met	Not met: zero same-residue pathogenic or likely pathogenic comparator variants were identified for p.Ser361Ile, so the VCEP's BLOSUM62 comparison cannot qualify.	cspec pm5_candidates vcep_mmc2 PMID:29706350
PM6	Not assessed	Not assessed: no documented presumed or assumed de novo observation, disease phenotype, family-history status, or parental testing is available.	cspec
PP1	Not assessed	Not assessed: no affected relatives, familial genotype-phenotype data, or observed meioses are documented for co-segregation analysis.	cspec
PP2	Met	Met at Supporting: this is a PTEN missense variant and the PTEN VCEP designates PP2 as applicable at pathogenic supporting strength.	cspec
PP3	Not met	Not met: the VCEP missense PP3 threshold is REVEL > 0.7, whereas this variant's REVEL score is 0.438.	cspec revel
PP4	N/A	Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 Use 2 rather than permitting PP4.	cspec
PP5	N/A	Not applicable: the PTEN VCEP prohibits PP5, and the reviewed PMID:25394175 does not mention this variant.	cspec PMID:25394175
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the VCEP BA1 threshold of >0.00056 (0.056%).	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no filtering allele frequency falls within either VCEP BS1 interval.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no homozygous observations or individual-level confirmation are available to satisfy the VCEP BS2 requirement.	cspec gnomad_v2 gnomad_v4
BS3	Met	Met at Supporting: high-confidence Table S2 phosphatase activity was 0.154 (>0), satisfying the VCEP's BS3_Supporting threshold.	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no affected family members with genotype data or documented non-segregation are available from one or more families.	cspec
BP1	N/A	Not applicable: the ClinGen PTEN Expert Panel specification explicitly marks BP1 Not Applicable.	cspec
BP2	Not assessed	Not assessed: no documented trans observation or at least three cis/phase-unknown observations with different pathogenic or likely pathogenic PTEN variants.	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	Met	Met at Supporting: the VCEP missense BP4 threshold is REVEL < 0.5, and this variant's REVEL score is 0.438.	cspec revel
BP5	Not assessed	Not assessed: no two qualifying cases with a highly penetrant alternate diagnosis and non-overlapping PTEN histories are documented.	cspec
BP6	N/A	Not applicable: the PTEN VCEP prohibits BP6 for this framework.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous or sufficiently distant intronic variants, whereas c.1082G>T is a missense substitution.	cspec

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