Variant classification summary

NM_000314.8:c.802-3T>A

PTEN · NP_000305.3:p.? · NM_000314.8

GRCh37: chr10:89720648 T>A · GRCh38: chr10:87960891 T>A

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PM2 supporting BP6 supporting benign

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.?

gnomAD AF

6.307039286547716e-07 (v4.1)

ClinVar

Likely Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.802-3T>A is an intronic variant at position -3 of the acceptor splice site of PTEN intron 7. It is present at extremely low frequency in gnomAD v4.1 (1/1,585,530 alleles, AF=6.3×10⁻⁷).

2

This variant has been classified as Likely Benign by the ClinGen PTEN Variant Curation Expert Panel (ClinVar ID 135912, 3-star expert panel review).

3

SpliceAI predicts no significant splicing impact (max delta score = 0.07). Computational tools collectively predict no effect on normal splicing, as noted in one clinical laboratory submission.

4

The variant is absent from gnomAD v2.1 and observed only once in gnomAD v4.1, meeting PTEN VCEP PM2_Supporting due to extremely low population frequency.

5

BP6 is applied at supporting benign level based on the ClinGen PTEN EP classification of Likely Benign (3-star expert panel review).

6

No functional splicing assay, de novo, segregation, or case-control data is available for this variant. The overall evidence profile supports a likely benign interpretation consistent with the expert panel classification.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_000314.8:c.802-3T>A is at position -3 of the intron 7 acceptor splice site, outside the canonical ±1,2 splice consensus positions. The PTEN VCEP PVS1 decision tree applies only to nonsense, frameshift, canonical GT-AG ±1,2 splice site disruptions, and exon deletions. Intronic variants at positions beyond ±2 are not eligible for PVS1.	cspec vcep_pvs1_decisiontree_pten
PS1	N/A	Variant is intronic (c.802-3T>A) and does not result in an amino acid change. No known pathogenic splice variant exists at the same nucleotide position for comparison. The PTEN VCEP PS1 rule applies to same amino acid changes or same-nucleotide splice variants with equal or greater predicted impact; neither condition is met.	cspec
PS2	Not met	No de novo occurrence data is available for this variant. The evidence packet contains no reports of confirmed or assumed de novo observations in patients with PTEN hamartoma tumor syndrome.
PS3	Not met	No RNA, mini-gene, or other splicing assay data is available for this variant. The mmc2.xlsx (Mighell et al. 2018, PMID:29706350) phosphatase activity assay applies only to missense variants. One ClinVar submission (SCV001362395, LabCorp) explicitly states 'functional studies have not been reported for this variant.' The SCV004835524 submission also notes 'to our knowledge, functional studies have not been reported for this variant.'	clinvar vcep_mmc2
PS4	Not met	No proband counting, case-control study, or PTEN specificity scoring data is available for this variant. The variant is present in ClinVar with submissions from several clinical laboratories, but no proband phenotype specificity scores have been calculated to meet the VCEP PS4 thresholds.	clinvar
PS5	Not met	PS5 requires a reputable source reporting the variant as pathogenic, with evidence not available for independent evaluation. The ClinVar expert panel (ClinGen PTEN VCEP) has classified this variant as Likely Benign, not Pathogenic. No reputable source reports this variant as pathogenic. Not met.	clinvar
PM1	N/A	This is an intronic variant at position c.802-3. The PTEN VCEP PM1 rule applies to amino acid residues within catalytic motifs (WPD loop residues 90-94, P-loop residues 123-130, TI-loop residues 166-168 of NP_000305.3). As an intronic variant, it does not alter any amino acid residue and cannot be assessed for hotspot or functional domain location.	cspec
PM2	Met	The variant is present at extremely low frequency in population databases, meeting the PTEN VCEP PM2_Supporting threshold. In gnomAD v4.1, it is observed in 1 of 1,585,530 alleles (AF=6.3×10⁻⁷; 0.000063%), which is well below the VCEP threshold of <0.001% (0.00001). The highest subpopulation frequency is in European (non-Finnish) at 1/1,168,048 alleles (AF=8.6×10⁻⁷; 0.000086%), also below the 0.002% subpopulation threshold. Absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM5	N/A	PM5 applies to missense variants with a different pathogenic missense change at the same amino acid residue. NM_000314.8:c.802-3T>A is an intronic splice site variant, not a missense change. The pm5_candidates.json confirms the variant is not eligible for classic same-residue missense PM5: 'variant class is not missense-like.'	pm5_candidates
PM6	Not met	No assumed or confirmed de novo observations are reported for this variant in ClinVar or the literature. The PTEN VCEP PM6 rule requires at minimum an assumed de novo occurrence in a proband with disease and no family history.
PP1	Not met	No co-segregation data is available for this variant. The PTEN VCEP PP1 rule requires at least 3-4 meioses for supporting-level evidence; no family studies or segregation analyses were identified in the evidence packet.
PP2	N/A	PP2 applies specifically to missense variants in genes with low rates of benign missense variation. NM_000314.8:c.802-3T>A is an intronic splice site variant, not a missense change.	cspec
PP3	Not met	The PTEN VCEP PP3 rule for splicing variants requires concordance of SpliceAI (score 0.5-1) and VarSeak (Class 4-5) predicting a splicing impact. SpliceAI max delta score for this variant is 0.07, far below the pathogenic range. No VarSeak data is available. The computational evidence does not support a deleterious effect on splicing; it supports the absence of impact.	spliceai
PP4	N/A	The PTEN VCEP specifies PP4 as Not applicable. Phenotype specificity was incorporated into the PS4 rule specifications by the expert panel.	cspec
PP5	Not met	The ClinVar expert panel classification for this variant is Likely Benign (ClinVar variation ID 135912), not Pathogenic or Likely Pathogenic. PP5 requires a reputable source reporting the variant as pathogenic. Although the PTEN VCEP marks PP5 as Not Applicable, even under the global ClinVar 3-star override rule, the EP classification of Likely Benign does not support PP5 (which requires a pathogenic assertion).	clinvar
BA1	Not met	The PTEN VCEP BA1 threshold requires gnomAD filtering allele frequency >0.056% (0.00056). The observed frequency in gnomAD v4.1 is 6.3×10⁻⁷ (0.000063%), far below the BA1 threshold.	gnomad_v4 cspec
BS1	Not met	The PTEN VCEP BS1_Strong threshold requires AF 0.0043%-0.056% (0.000043-0.00056) and BS1_Supporting requires AF 0.00043%-0.0043% (0.0000043-0.000043). The observed gnomAD v4.1 AF of 6.3×10⁻⁷ (0.000063%) falls below even the supporting threshold. The variant is too rare to meet BS1 at any strength.	gnomad_v4 cspec
BS2	Not met	The PTEN VCEP BS2 rule requires observation in the homozygous state in a healthy or PHTS-unaffected individual. gnomAD v4.1 reports 0 homozygotes for this variant. No homozygous observations are recorded in any database.	gnomad_v4 cspec
BS3	Not met	The PTEN VCEP BS3 rule for intronic variants requires RNA, mini-gene, or other splicing assay demonstrating no splicing impact. No functional splicing assay data is available for this variant. The Mighell et al. 2018 (PMID:29706350) phosphatase assay in mmc2.xlsx applies only to missense variants. SpliceAI computational prediction alone does not qualify as a functional assay under BS3.	cspec
BS4	Not met	No segregation data is available for this variant. The PTEN VCEP BS4 rule requires lack of segregation in affected family members; no family studies are present in the evidence packet.
BP1	N/A	The PTEN VCEP marks BP1 as Not applicable. This rule (missense variant in a gene where primarily truncating variants cause disease) is not applicable to PTEN per the expert panel specification.	cspec
BP2	Not met	No evidence of this variant occurring in trans with a pathogenic/likely pathogenic PTEN variant or in cis with multiple different pathogenic/likely pathogenic PTEN variants. The PTEN VCEP BP2 rule requires such observations.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a single nucleotide substitution in an intron.
BP4	Not met	The PTEN VCEP BP4 rule for intronic variants requires concordance of both SpliceAI (scores 0-0.2) and VarSeak (Class 1-2) predicting no splicing impact. SpliceAI max delta is 0.07, which falls in the benign range. However, VarSeak data is not available in the evidence packet, so the required concordance cannot be confirmed. One ClinVar submission (SCV001362395, LabCorp) notes '5/5 computational tools predict no significant impact on normal splicing,' consistent with a benign computational consensus, but without explicit VarSeak score the VCEP concordance requirement is not independently verifiable.	spliceai cspec clinvar
BP5	Not met	The PTEN VCEP BP5 rule requires at least two cases where the variant is found in individuals with an alternate molecular basis for disease (highly penetrant other gene/disorder, with no phenotypic overlap with PTEN). No such cases are reported in the evidence packet.
BP6	Met	Expert panel Clingen PTEN Variant Curation Expert Panel, Clingen classified as Likely benign.	clinvar
BP7	N/A	The PTEN VCEP BP7 rule for intronic variants requires the variant to be positioned at or beyond +7/-21 from the exon boundary. NM_000314.8:c.802-3T>A is at position -3 of intron 7 relative to exon 8, which is within the -1 to -21 zone (closer to the exon than position -21). This does not satisfy the VCEP positional requirement for BP7.	cspec

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