Classification rationale

PVS1PM2 Likely Pathogenic

PTEN c.634+1G>C

The PTEN c.634+1G>C (p.?) variant has been observed in somatic cancers in COSMIC (COSV64295775; 2 occurrences) and has been reported in ClinVar as pathogenic by three clinical laboratories.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1.² In silico splicing analysis predicts a marked effect on RNA processing, with a SpliceAI maximum delta score of 0.99, consistent with disruption of the canonical donor site.³

PVS1 + PM2 → Likely Pathogenic

1 cosmicclinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

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 review Pathogenic

NM_000314.8:c.634+1G>C disrupts the canonical +1 donor site of intron 6 in the biologically relevant transcript NM_000314.8. The PTEN-specific PVS1 decision tree indicates that canonical GT-AG splice-site disruption at or 5' to c.1121 (p.D375) is assigned PVS1; this variant is upstream of that threshold and is therefore consistent with PTEN loss of function under the PTEN VCEP rule.

PTEN VCEP PVS1 decision tree for NM_000314.8Variant location at c.634+1 canonical donor siteVariantValidator exon context showing intron 6 splice-site position

cspec ↗

PM2 Supporting review Pathogenic

The variant is absent from both gnomAD v2.1 and gnomAD v4.1, satisfying the PTEN PM2_Supporting population rarity rule.

Absent from gnomAD v2.1Absent from gnomAD v4.1PTEN-specific PM2 threshold

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 3 not met · 12 not assessed

Pathogenic

PS1 PTEN permits PS1 for a different variant at the same nucleotide position as a known pathogenic splicing variant if in silico impact is equal to or greater than the known pathogenic variant, but no same-position comparator variant with the necessary side-by-side evidence was documented.

PS2 No confirmed de novo occurrence with maternity and paternity established was documented.

PS3 PTEN allows PS3 for RNA, minigene, or other assays showing splicing impact, but no directly extracted assay result for NM_000314.8:c.634+1G>C was documented here.

PS4 The variant is present in ClinVar and reported in COSMIC, but no proband specificity scoring, case-count synthesis, or case-control analysis meeting PTEN PS4 thresholds was documented.

PM6 No presumed de novo occurrences in affected individuals without family history were documented.

PP1 No segregation data with informative meioses were documented.

PP3 SpliceAI predicts a strong splice effect with a maximum delta score of 0.99, but the PTEN PP3 rule for splicing variants requires concordance of SpliceAI and VarSeak.

Benign

BA1 The variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the PTEN BA1 frequency threshold.

BS1 The variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet PTEN BS1 or BS1_Supporting allele-frequency thresholds.

BS2 No homozygous observations in healthy or PTEN hamartoma tumor syndrome-unaffected individuals were documented.

BS3 No RNA, minigene, or other functional study demonstrating no splicing impact for this canonical splice donor variant was documented.

BS4 No nonsegregation data in one or more families were documented.

BP2 No phase data with other pathogenic or likely pathogenic PTEN variants were documented.

BP4 Benign computational evidence was not observed.

BP5 No evidence was documented showing that affected individuals carrying this variant had an alternate highly penetrant molecular diagnosis with nonoverlapping phenotype.

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

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

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 v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories).

ClinVar ↗

In silico

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

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; COSV64295775, n = 2 times).

Hotspots

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

Literature · how each cited paper was used

2papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

ACG clinical guideline: Genetic testing and management of hereditary gastrointes

PMID 25645574 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PVS1 Very Strong

Characterization of cryptic splicing in germline PTEN intronic variants in Cowde

PMID 28677221 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PVS1 Very Strong

Sources & reference links

6Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

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