PTEN

Final classification

Pathogenic

PVS1PS3PM2

PTEN

c.1027-2A>C

p.?

canonical splice

This variant

Transcript

NM_000314.8

HGVS · transcript:coding

NM_000314.8:c.1027-2A>C

GRCh38

chr10:87965285 A>C

GRCh37

chr10:89725042 A>C

Basis ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 criteria-combination framework: matched Rule1 (1 Pathogenic.Very Strong + Pathogenic.Strong >=1) with applied criteria: PVS1 very strong, PS3 strong, PM2 supporting; maps to Pathogenic. ▾

ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 criteria-combination framework: matched Rule1 (1 Pathogenic.Very Strong + Pathogenic.Strong >=1) with applied criteria: PVS1 very strong, PS3 strong, PM2 supporting; maps to Pathogenic.

Classification rationale

PVS1PS3PM2 Pathogenic

PTEN c.1027-2A>C canonical splice

NM_000314.8:c.1027-2A>C disrupts the canonical AG splice-acceptor of exon 9 (intron 8, -2 position), 5' to the p.D375 (c.1121) threshold, and is assigned PVS1 at very strong strength under the ClinGen PTEN Expert Panel PVS1 decision tree.¹ RNA analysis in patient-derived cells (RT-PCR and 3'RACE) demonstrated that this exact variant causes premature transcript termination within exon 8 at r.962 with polyadenylation, producing p.(Thr321_403del), meeting PS3 at strong strength.² The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting PM2 at supporting strength.³ The variant has been reported in ClinVar as Pathogenic by three clinical laboratories and Likely pathogenic by one clinical laboratory, consistent with a pathogenic interpretation.⁴ PVS1 alone (one very strong pathogenic criterion) satisfies the ClinGen PTEN Expert Panel combination rules for a Pathogenic classification.⁵

PVS1 + PS3 + PM2 → Pathogenic

1 vcep_pvs1_decisiontree_ptenpvs1_variant_assessmentPMID:28677221 ↗

2 PMID:28677221 ↗

3 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

4 clinvar ↗

5 cspec ↗final_classification_framework

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

PTEN NM_000314.8

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 16 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 · 3

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

NM_000314.8:c.1027-2A>C disrupts the canonical AG splice-acceptor of exon 9 (intron 8, -2 position), a GT-AG 1,2 splice site 5' to p.D375 (c.1121). Under the ClinGen PTEN Expert Panel PVS1 decision tree this is assigned full PVS1, and functional RNA analysis confirms abnormal transcript termination producing p.(Thr321_403del).

Canonical splice-acceptor disruption (AG>CG at c.1027-2) in a biologically-relevant transcript NM_000314.8Position 5' to the p.D375 (c.1121) threshold per PTEN PVS1 decision treeRNA analysis (28677221) shows premature transcript termination in exon 8 at r.962

PMID:28677221 ↗

✓

PS3 strong Pathogenic

Well-established RNA functional assay in patient-derived cells (RT-PCR and 3'RACE) demonstrated that this exact variant causes premature transcript termination within exon 8 at r.962 with polyadenylation, producing p.(Thr321_403del). This meets PTEN EP PS3 at strong strength (RNA assay showing impact on splicing).

Direct RNA analysis of the exact variant showing abnormal splicing/transcript terminationPredicted protein consequence p.(Thr321_403del)removing the C-terminal region

PMID:28677221 ↗cspec ↗

✓

PM2 supporting Pathogenic

The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PTEN EP PM2 threshold (allele frequency <0.00001 / 0.001%).

Absent from gnomAD v2.1Absent from gnomAD v4.1Absent from gnomAD-Canada v1.0

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied · 16 not met · 0 not assessed

Pathogenic

PS1 No established pathogenic variant at the same nucleotide position (c.1027-2) with a different nucleotide change was identified to satisfy the PS1 'same nucleotide position' rule.

PS2 No confirmed de novo observation (maternity and paternity confirmed) for this variant was read in the literature.

PS4 No case-control data, odds ratio, or proband specificity score establishing significantly increased prevalence of this variant in affected individuals was available.

PM1 The PTEN EP PM1 is defined for residues in the catalytic motifs (90-94, 123-130, 166-168).

PM6 No assumed de novo observation for this variant was read in the literature.

PP1 No co-segregation data (meioses) in affected family members was available for this variant.

PP3 The splice-effect prediction (SpliceAI max delta 0.994) is already captured by PVS1 and should not be double-counted.

Benign

BA1 The variant is absent from gnomAD, far below the BA1 filtering allele frequency threshold (>0.00056 / 0.056%).

BS1 The variant is absent from gnomAD, not present at the BS1 allele frequency range (0.000043-0.00056).

BS2 No homozygous observations in a healthy or PHTS-unaffected individual were identified.

BS3 Functional RNA analysis demonstrates a damaging effect on splicing (premature transcript termination), which is inconsistent with BS3.

BS4 No lack-of-segregation data in affected family members was available.

BP2 No observation of this variant in trans (or three observations in cis/unknown phase) with a pathogenic or likely pathogenic PTEN variant was identified.

BP4 SpliceAI predicts splice impact (max delta 0.994), inconsistent with a benign computational prediction.

BP5 No case with an alternate molecular basis for disease was identified.

BP7 BP7 requires an intronic variant at or beyond +7/-21 with no predicted splice impact.

N/A · 9 PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BP1 · BP3 · BP6

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 Pathogenic (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 427624)

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = -0.00757039.

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV109700531, n = 1 times).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

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. 8 further PMIDs triaged but not cited — see Sources & references.

Characterization of cryptic splicing in germline PTEN intronic variants in Cowden syndrome.

PMID 28677221 ↗ · Chen HJ et al. · 2017 Oct CLINVAR · splicing rna

Searched

c.1027-2A>C1027intron 8

Found

Characterizes cryptic splicing of germline PTEN intronic variants in Cowden syndrome. NM_000314.8:c.1027-2A>C (intron 8 splice-acceptor) causes premature transcript termination within exon 8 at r.962 with polyadenylation, predicted to produce p.(Thr321_403del), an abnormal RNA processing outcome.

Variant

✓ Names this variant — characterised directly

Applied to

→PVS1 met

→PS3 met

Why

Variant-specific RNA functional data confirmed abnormal splicing; referenced in PS3 (strong) and supports PVS1.

The transcript of this intron 8 mutation was cleaved within exon 8 at r.962 and a poly(A) tail was added directly onto the termination site.

Location Table 1; Results (fourth type of splicing defect); Supp. Fig. S2 · Context Patient-derived lymphoblastoid cells; RT-PCR and 3'RACE RNA analysis · full text

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 8 PMIDs not cited in assessment

11052475 ↗ Analysis of the PTEN gene mutation in polyposis syndromes and sporadic gastrointestinal tumors in Japanese patients. CLINVAR

17576681 ↗ Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. CLINVAR

19968660 ↗ Synchronous bilateral breast carcinoma in a patient with cowden syndrome: a case report with morphologic, immunohistochemical and genetic analysis. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

27477328 ↗ Immune dysregulation in patients with PTEN hamartoma tumor syndrome: Analysis of FOXP3 regulatory T cells. CLINVAR

9536098 ↗ Statistical features of human exons and their flanking regions. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR