PTENc.1027-2A>CPathogenic

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Variant interpretation report

PTEN c.1027-2A>C, p.?

NM_000314.8:c.1027-2A>C NP_000305.3:p.? View identifiers

Classification

Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About PTEN

No gene-level summary was recorded for this case.

Key facts

Condition: PTEN hamartoma tumor syndrome
Inheritance: Autosomal dominant
Evidence used: 1 very strong (pathogenic) · 1 strong (pathogenic) · 1 supporting (pathogenic)
Expert rules: ClinGen PTEN VCEP v3.2
Other laboratories (ClinVar): 3 Pathogenic · 1 Likely pathogenic
Pipeline record: 21 Aug 2026 · version 7.0.6

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): 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).
PS3 (strong): 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).
PM2 (supporting): 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%).

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.

01The reasoning

How it was classified

The recorded framework is ClinGen PTEN VCEP v3.2. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 3 Benign evidence criteria: 0

Pathogenic criteria applied · 3

PVS1Very strong

PVS1 · very strong

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).

PS3Strong

PS3 · strong

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).

PM2Supporting

PM2 · supporting

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%).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: 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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.994 maximum delta

Recorded SpliceAI maximum delta score: 0.994. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

4 reported laboratory submissions

3 Pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗

No screenshot for this evidence

Functional evidence

Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

Applied · PS3 → OncoKB ↗

Somatic evidence

1 recorded samples

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

Context only COSMIC ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen PTEN VCEP v3.2, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 16 not met · 0 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

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.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting PM2 at supporting strength.

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.

PVS1 alone (one very strong pathogenic criterion) satisfies the ClinGen PTEN Expert Panel combination rules for a Pathogenic classification.

Met · 3

PVS1 Very strongNM_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). Details ▾Hide ▴

Evidence considered

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

Sources

vcep_pvs1_decisiontree_ptenpvs1_variant_assessmentpvs1_gene_contextPMID:28677221 ↗

PS3 StrongWell-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). Details ▾Hide ▴

Evidence considered

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

Sources

PMID:28677221 ↗cspec ↗

PM2 SupportingThe 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%). Details ▾Hide ▴

Evidence considered

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

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 16 · evaluated, threshold not reached

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. Details ▾Hide ▴

Still missing

No comparator pathogenic variant at c.1027-2 with a different nucleotide substitution was identified.

PS2 No confirmed de novo observation (maternity and paternity confirmed) for this variant was read in the literature. A ClinVar submission with origin 'de novo' exists but no specific de novo report was reviewed. Details ▾Hide ▴

Still missing

ClinVar submission SCV003803858 lists origin 'de novo'
but the underlying de novo report was not available for review.

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

Still missing

No case-control or specificity-score data for this variant.

PM1 The PTEN EP PM1 is defined for residues in the catalytic motifs (90-94, 123-130, 166-168). This variant is a splice-acceptor substitution at c.1027-2, not located within a catalytic motif residue range. Details ▾Hide ▴

No further detail was recorded.

PM6 No assumed de novo observation for this variant was read in the literature. A ClinVar submission with origin 'de novo' exists but the specific report was not reviewed. Details ▾Hide ▴

Still missing

ClinVar submission SCV003803858 lists origin 'de novo'
but the underlying report was not available for review.

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

Still missing

No segregation data available.

PP3 The splice-effect prediction (SpliceAI max delta 0.994) is already captured by PVS1 and should not be double-counted. The PTEN EP PP3 rule additionally requires concordance of SpliceAI and VarSeak, and VarSeak was not available. Details ▾Hide ▴

Evidence considered

SpliceAI predicts splice impact (max delta 0.994)
but this evidence is consumed by PVS1 and VarSeak concordance is unavailable

Still missing

VarSeak prediction not available for required concordance.

Sources

spliceai ↗

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

Evidence considered

Absent from gnomAD

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

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

Evidence considered

Absent from gnomAD

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS2 No homozygous observations in a healthy or PHTS-unaffected individual were identified. Details ▾Hide ▴

Still missing

No homozygous observations.

BS3 Functional RNA analysis demonstrates a damaging effect on splicing (premature transcript termination), which is inconsistent with BS3. No functional study showing no damaging effect was identified. Details ▾Hide ▴

Evidence considered

RNA assay shows abnormal splicing
not benign effect

Sources

PMID:28677221 ↗

BS4 No lack-of-segregation data in affected family members was available. Details ▾Hide ▴

Still missing

No segregation data 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. Details ▾Hide ▴

Still missing

No in trans/in cis observations with pathogenic PTEN variants.

BP4 SpliceAI predicts splice impact (max delta 0.994), inconsistent with a benign computational prediction. The variant is a canonical splice-site disruption, not a benign splicing variant. Details ▾Hide ▴

Evidence considered

SpliceAI max delta 0.994 predicts splicing impact

Sources

spliceai ↗

BP5 No case with an alternate molecular basis for disease was identified. Details ▾Hide ▴

Still missing

No alternate molecular basis case data.

BP7 BP7 requires an intronic variant at or beyond +7/-21 with no predicted splice impact. This variant is at the canonical -2 splice-acceptor position with SpliceAI-predicted impact, so BP7 does not apply. Details ▾Hide ▴

Evidence considered

Variant is at the -2 canonical acceptor
not at/beyond +7/-21
SpliceAI predicts impact

Sources

spliceai ↗

Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴

PM3 VCEPPM3 applies to recessive disorders; PTEN hamartoma tumor syndrome is autosomal dominant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein length changes from in-frame indels or stop-loss; this is a canonical splice-site substitution. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to missense changes at a residue with an established pathogenic missense variant. This variant is a canonical splice-site substitution, not a missense change. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in a gene with a low rate of benign missense variation. This is a splice-site variant, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

PP4 VCEPThe ClinGen PTEN Expert Panel marks PP4 as Not Applicable; phenotype specificity is incorporated into the PS4 Use 2 specification. Details ▾Hide ▴

Sources

cspec ↗

PP5 VCEPThe ClinGen PTEN Expert Panel marks PP5 as Not Applicable, and the ClinVar record is 'criteria provided, single submitter' (no 3-star expert panel review), so the global PP5 supporting rule does not apply. Details ▾Hide ▴

No further detail was recorded.

BP1 VCEPThe ClinGen PTEN Expert Panel marks BP1 as Not Applicable. Details ▾Hide ▴

No further detail was recorded.

BP3 VCEPBP3 applies to in-frame indels in non-repeat regions; this is a splice-site substitution. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPThe ClinGen PTEN Expert Panel marks BP6 as Not Applicable for this VCEP, and the variant is not reported as benign by a reputable source. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not a criterion defined in the ClinGen PTEN Expert Panel specifications v3.2 nor in the standard ACMG/AMP 2015 criteria. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: PTEN
Transcript: NM_000314.8
Coding (HGVS c.): NM_000314.8:c.1027-2A>C
Protein (HGVS p.): NP_000305.3:p.?
GRCh38: chr10:87965285 A>C
GRCh37: chr10:89725042 A>C
ClinVar: 427624, 635376, 427581
COSMIC: COSV109700531

Gene diagram

Every interpreted variant in PTEN, mapped onto the exon structure of NM_000314.8. Select a row to find it on the plot.

PTENNM_000314.8

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in PTEN — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +2 bp

0.994

SpliceAI acceptor gainat +8 bp

0.246

SpliceAI donor lossat +79 bp

0.002

SpliceAI donor gainat +181 bp

0.006

Pangolin splice lossmagnitude shown

-0.911

Pangolin splice gain

0.616

Other predictors

REVEL: Not available
BayesDel: -0.008

How the predictions were used

Evidence considered

SpliceAI predicts splice impact (max delta 0.994)
but this evidence is consumed by PVS1 and VarSeak concordance is unavailable

Still missing

VarSeak prediction not available for required concordance.

Sources

spliceai ↗

Evidence considered

SpliceAI max delta 0.994 predicts splicing impact

Sources

spliceai ↗

Evidence considered

Variant is at the -2 canonical acceptor
not at/beyond +7/-21
SpliceAI predicts impact

Sources

spliceai ↗

Statement

In silico

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

9 paper records listed. 1 cited in the classification.

Cited in the classification

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

Chen HJ et al. · 2017 Oct

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.
→ PVS1 → PS3 Names this variant
PMID 28677221 ↗
Source detail

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

Other recorded publications

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

Negoro K et al. · 2000

Screens PTEN mutations in Japanese patients with gastrointestinal polyposis and sporadic tumors. NM_000314.8:c.1027-2A>C was not identified in the abstract.
Does not name this variant
PMID 11052475 ↗
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E et al. · 2007

Reviews mutation patterns of aberrant 5' splice sites across 166 human disease genes. NM_000314.8:c.1027-2A>C was not identified in this paper.
Does not name this variant
PMID 17576681 ↗
Synchronous bilateral breast carcinoma in a patient with cowden syndrome: a case report with morphologic, immunohistochemical and genetic analysis.

Peiró G et al. · 2010

Case report of synchronous bilateral breast carcinoma in a patient with Cowden syndrome. NM_000314.8:c.1027-2A>C was not identified in the abstract.
Does not name this variant
PMID 19968660 ↗
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.

ACMG/AMP standards and guidelines for sequence variant interpretation. NM_000314.8:c.1027-2A>C is not mentioned.
Does not name this variant
PMID 25741868 ↗
Immune dysregulation in patients with PTEN hamartoma tumor syndrome: Analysis of FOXP3 regulatory T cells.

Chen HH et al. · 2017

Studies FOXP3 regulatory T cells in patients with PTEN hamartoma tumor syndrome. NM_000314.8:c.1027-2A>C was not identified in this paper.
Does not name this variant
PMID 27477328 ↗
Statistical features of human exons and their flanking regions.

Survey of statistical features of human exons and their flanking regions. NM_000314.8:c.1027-2A>C was not identified in this paper.
Does not name this variant
PMID 9536098 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.

National Society of Genetic Counselors cancer genetic counseling recommendations. NM_000314.8:c.1027-2A>C is not mentioned.
Does not name this variant
PMID 15604628 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Sherloc refinement of the ACMG-AMP variant classification criteria. NM_000314.8:c.1027-2A>C is not mentioned.
Does not name this variant
PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.994 Open source ↗

ClinVar 3 Pathogenic · 1 Likely pathogenic Open source ↗

COSMIC Captured COSMIC source record Open source ↗

ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 427624)

In silico

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

Somatic

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