Variant classification summary

NM_000314.8:c.254-3C>G

PTEN · NP_000305.3:p.? · NM_000314.8

GRCh37: chr10:89692767 C>G · GRCh38: chr10:87933010 C>G

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1, with allele frequency 0 below the PTEN VCEP threshold.

Final determination: Under the PTEN Expert Panel Version 3.2 framework, PM2 supporting alone satisfies no pathogenic or benign combination rule, so the variant is classified as VUS.

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	Not applicable: c.254-3C>G is a noncanonical intronic variant with unknown consequence, outside the PTEN VCEP decision tree's named PVS1 paths.	cspec vcep_pvs1_decisiontree_pten
PS1	Not assessed	Not assessed: no pathogenic same-position splice comparator or matched in-silico impact is available for c.254-3C>G.	cspec
PS2	Not assessed	Not assessed: no proband, parental-testing, family-history, or de novo observations are documented for this variant.	cspec
PS3	Not assessed	Not assessed: no variant-specific RNA or other functional assay result was available, and the Mighell Table S2 search had no matching c.254-3C>G or p.? entry.	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no affected-control comparison or phenotype-specific proband score is available to evaluate the PTEN VCEP PS4 rule.	cspec gnomad_v2 gnomad_v4
PM1	Not assessed	Not assessed: c.254-3C>G has protein consequence p.? and cannot be placed within the VCEP's catalytic motifs 90-94, 123-130, or 166-168.	cspec
PM2	Met	Met at supporting strength: gnomAD v2.1 and v4.1 report absence, corresponding to allele frequency 0 below the <0.00001 PM2 threshold.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP explicitly designates PM3 as not applicable.	cspec
PM4	N/A	Not applicable: p.? provides no established protein-length change, and PM4 is limited to in-frame insertions/deletions or stop-loss variants.	cspec
PM5	N/A	Not applicable: c.254-3C>G is intronic with protein consequence p.?, whereas PM5 requires a missense change at an amino-acid residue.	cspec
PM6	Not assessed	Not assessed: no assumed de novo occurrence, affected proband, or parental-testing status is documented for this variant.	cspec
PP1	Not assessed	Not assessed: zero affected-family meioses or segregation observations are documented, so no PP1 threshold can be met.	cspec
PP2	N/A	Not applicable: c.254-3C>G is intronic with protein consequence p.?, not the missense variant required by PP2.	cspec
PP3	Not assessed	Not assessed: PTEN's splicing rule requires concordant SpliceAI and VarSeak predictions, but only a SpliceAI max delta of 0.962 is available.	cspec spliceai
PP4	N/A	Not applicable: the PTEN VCEP marks PP4 as Not Applicable and routes phenotype-specific evidence through PS4.	cspec
PP5	N/A	Not applicable: the PTEN VCEP marks PP5 as Not Applicable, so no PP5 assertion is allowed.	cspec
BA1	Not met	Not met: gnomAD v2.1 and v4.1 report absence, corresponding to observed allele frequency 0, below the >0.00056 BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 report allele frequency 0, below the BS1 supporting interval beginning at 0.0000043.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v2.1 and v4.1 report no variant observations, so no homozygous healthy-individual observation exists for BS2.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific no-impact splicing assay was available, and the Mighell Table S2 search had no matching c.254-3C>G or p.? entry.	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no affected-family non-segregation observation is documented, so neither the one-family nor two-family BS4 rule applies.	cspec
BP1	N/A	Not applicable: the PTEN VCEP explicitly excludes BP1 for PTEN.	cspec
BP2	Not assessed	Not assessed: no documented cis, trans, or phase-unknown observations with pathogenic or likely pathogenic PTEN variants are available.	cspec
BP3	N/A	Not applicable: the PTEN VCEP explicitly designates BP3 as not applicable.	cspec
BP4	Not assessed	Not assessed: PTEN's splicing rule requires concordant SpliceAI and VarSeak predictions, but only a SpliceAI max delta of 0.962 is available.	cspec spliceai
BP5	Not assessed	Not assessed: no documented alternate molecular basis, highly penetrant disorder, and non-overlapping PTEN history satisfy the BP5 rule.	cspec
BP6	N/A	Not applicable: the PTEN VCEP marks BP6 as Not Applicable, so no BP6 assertion is allowed.	cspec
BP7	N/A	Not applicable: c.254-3 lies within the VCEP's excluded intronic interval, rather than at or beyond -21.	cspec

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