Variant classification summary

NM_000314.8:c.254-1G>A

PTEN · NP_000305.3:p.? · NM_000314.8

GRCh37: chr10:89692769 G>A · GRCh38: chr10:87933012 G>A

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.?

gnomAD AF

6.220677282459805e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: the canonical -1 splice-site change is predicted to cause a frameshifted exon-5 skipping transcript upstream of the NMD threshold.

2

PM2 supporting: the gnomAD v4.1 allele frequency is below the PTEN VCEP threshold, with zero homozygotes reported.

Final determination: Rule20 of the ClinGen PTEN Expert Panel Specifications combines one pathogenic very-strong criterion with one pathogenic supporting criterion to yield a Likely Pathogenic classification.

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 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.	cspec vcep_pvs1_decisiontree_pten pvs1_variant_assessment
PS1	Not assessed	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.	cspec spliceai
PS2	Not assessed	Not assessed: no documented proband-level de novo observation, parental testing, or family-history status is available to evaluate the PS2 thresholds.	cspec
PS3	Not assessed	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.	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no variant-specific proband phenotype, specificity score, or case-control enrichment statistic is available for applying the PTEN VCEP PS4 rule.	cspec
PM1	N/A	Not applicable: The variant has no encoded amino-acid residue, while the VCEP PM1 domains are limited to residues 90-94, 123-130, and 166-168.	cspec
PM2	Met	Met at supporting strength: gnomAD v4.1 total AF is 6.220677282459805e-07, below the <0.00001 PM2 threshold, with 0 homozygotes.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP explicitly marks PM3 as "Not Applicable."	cspec
PM4	N/A	Not applicable: the variant is a canonical splice-site substitution with a predicted frameshift, whereas PTEN PM4 covers in-frame length changes, stop-loss, catalytic-motif changes, or protein extension.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: PM5 requires a missense change at an amino-acid residue, but this variant is a canonical splice-site change with protein consequence p.?.	cspec
PM6	Not assessed	Not assessed: no presumed de novo proband observation, family-history status, or parental-confirmation details are documented for applying PM6.	cspec
PP1	Not assessed	Not assessed: no affected relatives or informative meioses are documented, so the PP1 segregation thresholds cannot be applied.	cspec
PP2	N/A	Not applicable: PP2 requires a missense variant, whereas this variant is a canonical splice-site change with protein consequence p.?.	cspec
PP3	Not assessed	Not assessed: the rule requires concordant SpliceAI and VarSeak predictions, but only SpliceAI is available, with maximum delta 0.993.	cspec spliceai
PP4	N/A	Not applicable: the PTEN VCEP explicitly designates PP4 as not applicable and incorporates phenotype specificity into PS4 Use 2.	cspec
PP5	N/A	Not applicable: the PTEN VCEP prohibits use of PP5, so ClinVar or published pathogenic classifications cannot support this criterion.	cspec
BA1	Not assessed	Not assessed: gnomAD filtering allele frequency is unavailable, although total AF is 6.220677282459805e-07 versus the >0.00056 BA1 threshold.	cspec gnomad_v4
BS1	Not assessed	Not assessed: gnomAD filtering allele frequency is unavailable, while total AF is 6.220677282459805e-07 below the 0.0000043 BS1-supporting lower bound.	cspec gnomad_v4
BS2	Not met	Not met: gnomAD v4.1 reports 0 homozygotes, but the rule requires at least one homozygous observation in a healthy or PHTS-unaffected individual.	cspec gnomad_v4
BS3	Not assessed	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.	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no affected-family non-segregation observation is documented for evaluating BS4 at supporting or strong strength.	cspec
BP1	N/A	Not applicable: The PTEN VCEP explicitly states that BP1 is not applicable to PTEN.	cspec
BP2	Not assessed	Not assessed: no documented pathogenic PTEN variant in cis or trans, or phase result, establishes either VCEP BP2 pathway.	cspec
BP3	N/A	Not applicable: the PTEN VCEP explicitly states that BP3 is not applicable to PTEN, regardless of the variant's repeat-region context.	cspec
BP4	Not assessed	Not assessed: the rule requires concordant benign SpliceAI and VarSeak predictions, but SpliceAI's maximum delta is 0.993 and VarSeak is unavailable.	cspec spliceai
BP5	Not assessed	Not assessed: no two cases with an alternate highly penetrant molecular diagnosis and documented non-overlapping PTEN history meet the BP5 requirements.	cspec
BP6	N/A	Not applicable: the PTEN VCEP prohibits use of BP6, regardless of any reputable-source benign report.	cspec
BP7	N/A	Not applicable: c.254-1G>A is an intronic -1 splice-site variant, outside BP7's scope of intronic variants at or beyond -21.	cspec

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