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

VUS

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

PM2 supporting: gnomAD v4.1 allele frequency is 6.22e-7, below the PTEN VCEP threshold of <0.00001.

Final determination: Under the ClinGen PTEN VCEP Version 3.2 criteria-combination rules, PM2 supporting alone does not satisfy a pathogenic or benign rule, so the classification remains 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	Not assessed	Not assessed: canonical splice disruption has SpliceAI DS_AL 0.993, but the required NMD outcome and resulting reading-frame consequence are not established.	cspec vcep_pvs1_decisiontree_pten pvs1_variant_assessment spliceai
PS1	Not assessed	Not assessed: the canonical splice variant lacks a documented same-position pathogenic comparator and the required comparative in-silico evidence.	cspec
PS2	Not assessed	Not assessed: no documented proband-level de novo observation with both maternity and paternity confirmed and no family history.	cspec
PS3	Not assessed	Not assessed: no RNA, mini-gene, or other splicing assay result is available for canonical splice-site variant c.254-1G>A.	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no variant-specific case-control statistics or PTEN phenotype-specificity scores are available to compare with the VCEP PS4 thresholds.	cspec
PM1	N/A	Not applicable: c.254-1G>A is a canonical splice-site variant with protein consequence p.?, not a residue-level change within a listed PTEN domain.	cspec
PM2	Met	Met at supporting: gnomAD v4.1 total allele frequency is 6.22e-7, below the PTEN VCEP PM2 threshold of <0.00001.	cspec gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: the PTEN VCEP explicitly excludes PM3 for PTEN, regardless of available phase or affected-proband observations.	cspec
PM4	N/A	Not applicable: c.254-1G>A is a splice-site substitution, not an in-frame insertion/deletion or stop-loss protein-length change.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: the variant is canonical splice-site c.254-1G>A with protein consequence p.?, not a missense change at an amino-acid residue.	cspec
PM6	Not assessed	Not assessed: no documented assumed or presumed de novo observation in a patient with disease and no family history.	cspec
PP1	Not assessed	Not assessed: no affected relatives carrying the variant or informative meiosis count is documented.	cspec
PP2	N/A	Not applicable: PP2 requires a missense variant, whereas c.254-1G>A is a canonical splice-site variant with protein consequence p.?.	cspec
PP3	Not assessed	Not assessed: SpliceAI max delta 0.993 meets the VCEP pathogenic range, but the required concordant VarSeak result is unavailable.	cspec spliceai
PP4	N/A	Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 Use 2 rather than allowing PP4.	cspec
PP5	N/A	Not applicable: the PTEN VCEP explicitly prohibits use of PP5 under the ClinGen SVI VCEP recommendation.	cspec
BA1	Not met	Not met: gnomAD v4.1 total allele frequency is 6.22e-7, far below the PTEN VCEP BA1 threshold of >0.00056.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 total allele frequency is 6.22e-7, below the PTEN VCEP BS1 supporting lower boundary of 0.0000043.	cspec gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes, with no qualifying healthy or PHTS-unaffected homozygous observation available for the PTEN VCEP rule.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no RNA, mini-gene, or other assay demonstrates no splicing impact for canonical splice-site variant c.254-1G>A.	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no affected relatives lacking the variant are documented in one or more families.	cspec
BP1	N/A	Not applicable: the PTEN VCEP explicitly marks BP1 as Not Applicable.	cspec
BP2	Not assessed	Not assessed: no co-occurring pathogenic or likely pathogenic PTEN variant with documented trans, cis, or unknown phase is available.	cspec
BP3	N/A	Not applicable: the PTEN VCEP explicitly designates BP3 as not applicable to PTEN.	cspec
BP4	Not assessed	Not assessed: SpliceAI max delta 0.993 is outside the VCEP benign range, and the required VarSeak result is unavailable for concordance.	cspec spliceai
BP5	Not assessed	Not assessed: no two cases with a highly penetrant alternate diagnosis and demonstrably non-overlapping PTEN history are documented.	cspec
BP6	N/A	Not applicable: the PTEN VCEP explicitly prohibits use of BP6 under the ClinGen SVI VCEP recommendation.	cspec
BP7	N/A	Not applicable: c.254-1G>A is a canonical splice-site variant at intronic position -1, outside BP7's required at-or-beyond -21/+7 location scope.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.