Classification rationale

PVS1PM2 Likely Pathogenic

PTEN c.254-1G>A canonical_splice · exon 4i

PVS1 very strong: the canonical -1 splice-site change is predicted to cause a frameshifted exon-5 skipping transcript upstream of the NMD threshold. PM2 supporting: the gnomAD v4.1 allele frequency is below the PTEN VCEP threshold, with zero homozygotes reported.

PVS1 + PM2 → Likely Pathogenic

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.

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

PTEN NM_000314.8

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 15 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 · 2

Strength Supporting Moderate Strong Very strong

PVS1 very strong Pathogenic

Met at very strong: canonical -1 acceptor disruption causes a predicted exon-5 frameshift after loss of 239 coding nucleotides and lies 5' of the PTEN c.1121 NMD threshold.

pvs1_variant_assessment records NM_000314.8:c.254-1G>A as a canonical splice variant at the acceptor (-1), affecting exon 5 of 9 in the biologically relevant transcript.pvs1_variant_assessment records exon 5 as c.254_492, with 239 coding nucleotides; exon skipping removes 239 nt (239 % 3 = 2) and shifts the reading frame.PVS1_DecisionTree_PTEN.pdf, page 1: the GT-AG +/-1,2 splice-site branch assigns PVS1 when exon skipping or cryptic splice-site use disrupts the reading frame and is predicted to undergo NMD, the disruption is at or 5' to p.D375 (c.1121), and the exon is present in NM_000314.8.

cspec ↗vcep_pvs1_decisiontree_pten ↗

PM2 supporting Pathogenic

Met at supporting strength: gnomAD v4.1 total AF is 6.220677282459805e-07, below the <0.00001 PM2 threshold, with 0 homozygotes.

ClinGen PTEN VCEP Version 3.2 PM2 rule: databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population; if multiple alleles are present within any subpopulation, that subpopulation allele frequency must be <0.00002 (0.002%).gnomAD v4.1 reports total AF 6.220677282459805e-07 (1/1607542 alleles), highest listed subpopulation AF 8.516291665956976e-07 (1/1174220 alleles), and 0 homozygotes.gnomAD v2.1 reports the variant absent; the available gnomAD v2.1 non-cancer and v3.1 non-cancer queries also report absence.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 1 not met · 14 not assessed

Pathogenic

PS1 Not assessed: SpliceAI is 0.993, but no known pathogenic comparator at the same nucleotide position is available for the VCEP's required equal-or-greater comparison.

PS2 Not assessed: no documented proband-level de novo observation, parental testing, or family-history status is available to evaluate the PS2 thresholds.

PS3 Not assessed: no qualifying splice assay result is available, and the VCEP's phosphatase threshold applies to missense assay data absent for this canonical splice-site variant.

PS4 Not assessed: no variant-specific proband phenotype, specificity score, or case-control enrichment statistic is available for applying the PTEN VCEP PS4 rule.

PM6 Not assessed: no presumed de novo proband observation, family-history status, or parental-confirmation details are documented for applying PM6.

PP1 Not assessed: no affected relatives or informative meioses are documented, so the PP1 segregation thresholds cannot be applied.

PP3 Not assessed: the rule requires concordant SpliceAI and VarSeak predictions, but only SpliceAI is available, with maximum delta 0.993.

Benign

BA1 Not assessed: gnomAD filtering allele frequency is unavailable, although total AF is 6.220677282459805e-07 versus the >0.00056 BA1 threshold.

BS1 Not assessed: gnomAD filtering allele frequency is unavailable, while total AF is 6.220677282459805e-07 below the 0.0000043 BS1-supporting lower bound.

BS2 Not met: gnomAD v4.1 reports 0 homozygotes, but the rule requires at least one homozygous observation in a healthy or PHTS-unaffected individual.

BS3 Not assessed: no benign splicing assay demonstrates no impact, and the VCEP's phosphatase criterion applies to missense assay data absent for this canonical splice-site variant.

BS4 Not assessed: no affected-family non-segregation observation is documented for evaluating BS4 at supporting or strong strength.

BP2 Not assessed: no documented pathogenic PTEN variant in cis or trans, or phase result, establishes either VCEP BP2 pathway.

BP4 Not assessed: the rule requires concordant benign SpliceAI and VarSeak predictions, but SpliceAI's maximum delta is 0.993 and VarSeak is unavailable.

BP5 Not assessed: no two cases with an alternate highly penetrant molecular diagnosis and documented non-overlapping PTEN history meet the BP5 requirements.

N/A · 11 PM1 · PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BP1 · BP3 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.22068e-07; MAF= 0.00006%, 1/1607542 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.51629e-07; MAF= 0.00009%, 1/1174220 alleles, homozygotes = 0).

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

6.2e-05% · 1 / 1,607,542
0 hom

European (non-Finnish)

1 / 1,174,220

8.5e-05%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

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 (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 377376)

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.31948.

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; COSV100910231, n = 1 times).

Hotspots

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

COSMIC ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 7 PMIDs not cited in assessment

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

28475857 ↗ Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability. CLINVAR

17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR

23519317 ↗ Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. CLINVAR

23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. CLINVAR

25190698 ↗ Genetic/familial high-risk assessment: breast and ovarian, version 1.2014. CLINVAR

27854360 ↗ Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. CLINVAR

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