Variant classification summary

NM_000314.8:c.165-1G>A

PTEN · NP_000305.3:p.? · NM_000314.8

GRCh37: chr10:89685269 G>A · GRCh38: chr10:87925512 G>A

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Pathogenic

PVS1 strong PM2 supporting PP5 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.?

gnomAD AF

ClinVar

Likely Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic evidence: PVS1 strong is assigned for reading-frame-preserving alteration of critical PTEN exon 3.

2

Pathogenic evidence: PM2 supporting is met because the variant is absent from qualifying gnomAD datasets.

3

Pathogenic evidence: PP5 supporting is recorded from an expert-panel ClinVar likely pathogenic assertion.

Final determination: The PTEN VCEP Version 3.2 Rule12 combination of at least one strong pathogenic criterion and at least two supporting pathogenic criteria yields Likely Pathogenic.

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	Met	Met, strong: VCEP assigns PVS1_Strong for reading-frame-preserving skipping of critical exon 3 after this canonical acceptor splice-site disruption.	cspec vcep_pvs1_decisiontree_pten pvs1_variant_assessment spliceai
PS1	Not assessed	Not assessed: c.165-1G>C caused exon 3 skipping, but its pathogenic designation and comparable in silico score are unavailable for comparison with SpliceAI 0.976.	cspec PMID:28677221
PS2	Not assessed	Not assessed: no documented germline de novo observation with confirmed maternity and paternity and no family history is available for this variant.	cspec
PS3	Not assessed	Not assessed: no VCEP-qualifying functional assay for c.165-1G>A was available, and mmc2.xlsx contained no matching c.165-1G>A or p.? entry.	cspec vcep_mmc2 PMID:28677221 PMID:34518631
PS4	Not assessed	Not assessed: no variant-specific case-control statistics or phenotype-specificity score is available to compare with the PTEN VCEP PS4 thresholds.	cspec PMID:21194675
PM1	N/A	Not applicable: PM1 names PTEN residues 90-94, 123-130, and 166-168, while c.165-1G>A is a splice-site variant with protein consequence p.?.	cspec
PM2	Met	Met at Supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PTEN VCEP population-frequency requirement of <0.00001 (0.001%).	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP explicitly states that PM3 is not applicable to PTEN.	cspec
PM4	N/A	Not applicable: PM4 covers in-frame insertions/deletions or stop-loss protein length changes, whereas this variant is a canonical splice-site substitution.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: PM5 requires a missense change at an amino-acid residue, but c.165-1G>A is a canonical splice-site variant with protein consequence p.?.	cspec
PM6	Not assessed	Not assessed: zero countable assumed de novo observations with disease and no family history are documented for this variant.	cspec
PP1	Not assessed	Not assessed: no variant-specific affected-relative segregation or meiosis count is documented, so the 3-meiosis supporting threshold cannot be evaluated.	cspec PMID:9467011
PP2	N/A	Not applicable: PP2 requires a missense variant, whereas c.165-1G>A is a canonical splice-site change.	cspec
PP3	Not assessed	Not assessed: SpliceAI max delta 0.976 is available, but the PTEN rule requires concordance with the named VarSeak predictor, which is unavailable.	cspec spliceai
PP4	N/A	Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 Use 2 rather than applying PP4.	cspec
PP5	Met	Not applicable: the PTEN VCEP prohibits use of PP5, regardless of the available pathogenic ClinVar assertions.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than having a filtering allele frequency above the 0.00056 (0.056%) BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no allele frequency in either the 0.000043–0.00056 or 0.0000043–0.000043 BS1 intervals.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no homozygous observation in a healthy or PHTS-unaffected individual, homozygote count, or clinical-status evidence is available.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no VCEP-qualifying benign functional or splicing assay for c.165-1G>A was available, and mmc2.xlsx contained no matching c.165-1G>A or p.? entry.	cspec vcep_mmc2 PMID:28677221 PMID:34518631
BS4	Not assessed	Not assessed: no affected-family non-segregation observation is documented for this variant, so neither the one-family nor two-family threshold can be evaluated.	cspec
BP1	N/A	Not applicable: the PTEN VCEP explicitly marks BP1 as Not Applicable.	cspec
BP2	Not assessed	Not assessed: no documented trans observation or at least three qualifying cis/phase-unknown observations with different pathogenic PTEN variants are available.	cspec
BP3	N/A	Not applicable: the PTEN VCEP explicitly designates BP3 as Not Applicable for this framework.	cspec
BP4	Not assessed	Not assessed: SpliceAI max delta 0.976 predicts splice impact, but BP4 requires concordance with the named VarSeak predictor and that result is unavailable.	cspec spliceai
BP5	Not assessed	Not assessed: no two cases with a highly penetrant alternate diagnosis and non-overlapping PTEN personal or family histories are documented.	cspec
BP6	N/A	Not applicable: the PTEN VCEP prohibits use of BP6, regardless of whether a reputable benign source is available.	cspec
BP7	N/A	Not applicable: c.165-1G>A is a canonical splice-acceptor variant at -1, outside BP7's synonymous or intronic at-or-beyond +7/-21 scope.	cspec

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