Classification rationale

BA1BS2 Benign

PTEN c.-491_-486dup unknown · exon 1

Benign: gnomAD v4.1 allele frequency 0.001394 exceeds the PTEN BA1 threshold of >0.00056. Benign evidence: gnomAD v4.1 reports three homozygous observations, meeting PTEN BS2 supporting criteria.

BA1 + BS2 → Benign

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 · 12 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

BA1 stand-alone Benign

Met: gnomAD v4.1 all-comers AF 0.001394 exceeds the PTEN BA1 threshold of >0.00056.

PTEN VCEP Version 3.2 specifies BA1 when gnomAD filtering allele frequency is >0.00056.The default all-comers gnomAD source is appropriate because the PTEN specification does not mandate a non-cancer or exome-only population subset.gnomAD v4.1 reports AF 0.0013939683 (526/377340), Finnish population AF 0.006070159, and grpmax FAF 0.00127765.

cspec ↗gnomad_v4 ↗gnomad_v2 ↗

BS2 supporting Benign

Met at supporting strength: gnomAD v4.1 reports three homozygotes, exceeding the PTEN rule requiring two observations without clinical data.

PTEN VCEP Version 3.2 specifies BS2 strong for one confirmed homozygous observation or two unconfirmed observations, and supporting for two homozygous observations without clinical data.gnomAD v4.1 reports three homozygotes overall: two in the Finnish population and one in the European non-Finnish population.The gnomAD record provides no individual clinical or PHTS-unaffected status, so the VCEP supporting rule for homozygous observations without clinical data applies.

cspec ↗gnomad_v4 ↗gnomad_v2 ↗

Assessed · not applied · 4 not met · 8 not assessed

Pathogenic

PS2 Not assessed: no documented de novo proband or parental testing was available to satisfy the PTEN PS2 requirement for confirmed maternity and paternity.

PS3 Not assessed: mmc2.xlsx has no entry for c.-491_-486dup, p.?, or p.(=), and no qualifying variant-specific functional assay result is available.

PS4 Not assessed: no exact-variant case-control odds ratio, p value, confidence interval, or PTEN phenotype-specific proband score is available for comparison with the PS4 thresholds.

PM2 Not met: gnomAD v4.1 AF 0.001394 is far above the PTEN PM2 threshold of <0.00001.

PM4 Not met: predicted protein consequence NP_000305.3:p.(=) shows no protein-length change, and the variant is upstream of all PTEN catalytic motifs.

PM6 Not assessed: zero documented assumed de novo observations were available against the PTEN PM6 minimum of one disease proband without confirmed maternity and paternity.

PP1 Not assessed: zero informative meioses or affected relatives were documented, below the PTEN PP1 Supporting threshold of 3 or 4 meioses.

Benign

BS1 Not met: gnomAD v4.1 AF 0.001394 is above the PTEN BS1 upper limit of 0.00056 and meets BA1 instead.

BS3 Not assessed: mmc2.xlsx has no entry for c.-491_-486dup, p.?, or p.(=), and no qualifying benign functional or splicing assay result is available.

BS4 Not assessed: no affected-family segregation comparison was documented, while the PTEN BS4 Supporting threshold requires lack of segregation in one family.

BP2 Not met: no documented trans observation or at least three cis/unknown-phase observations with pathogenic or likely pathogenic PTEN variants.

BP5 Not assessed: no two qualifying cases with a highly penetrant alternate molecular diagnosis and non-overlapping personal or family history are documented.

N/A · 14 PVS1 · PS1 · PM1 · PM3 · PM5 · PP2 · PP3 · PP4 · PP5 · BP1 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.00139397; MAF= 0.13940%, 526/377340 alleles, homozygotes = 3) and has highest observed frequency in the European (Finnish) population (AF= 0.00607016; MAF= 0.60702%, 181/29818 alleles, homozygotes = 2); grpmax FAF= 0.00127765.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00199322; MAF= 0.19932%, 60/30102 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.00772082; MAF= 0.77208%, 25/3238 alleles, homozygotes = 0); grpmax FAF= 0.00134244.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.001053565487412665, 19/18034 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.14% · 526 / 377,340
3 hom · FAF 0.13%

European (Finnish) 181 / 29,818	0.61% 2 hom
Remaining individuals 24 / 16,700	0.14%
European (non-Finnish) 302 / 214,428	0.14% 1 hom
African/African American 13 / 46,540	0.028%
Admixed American 6 / 21,582	0.028%

+ 5 not observed (Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.2% · 60 / 30,102
0 hom · FAF 0.13%

European (Finnish) 25 / 3,238	0.77%
Remaining individuals 3 / 1,030	0.29%
European (non-Finnish) 28 / 14,816	0.19%
African/African American 4 / 8,400	0.048%

+ 4 not observed (Admixed American, Ashkenazi Jewish, East Asian, South Asian)

gnomAD Canada 🇨🇦

0.11% · 19 / 18,034
0 hom · FAF 0.11%

indel · split

European (non-Finnish)

19 / 11,502

0.17%

+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as benign (1 clinical laboratory). (ClinVarID = 492721)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).

SpliceAI ↗

Functional No data

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

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

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 · 2 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

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

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