Variant classification summary

NM_000314.8:c.771C>A

PTEN · NP_000305.3:p.(Phe257Leu) · NM_000314.8

GRCh37: chr10:89717746 C>A · GRCh38: chr10:87957989 C>A

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PS3 moderate PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Phe257Leu)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 Moderate: high-confidence PTEN F257L functional score of -2.055963973 supports impaired phosphatase activity.

2

PM2 Supporting: the variant is absent from gnomAD v2.1 and v4.1.

Final determination: Under the PTEN Expert Panel Version 3.2 combining rules, one Moderate criterion plus one Supporting criterion does not meet a Pathogenic, Likely Pathogenic, Benign, or Likely Benign rule, so the call is 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.771C>A causes a missense change, whereas the PTEN PVS1 decision tree covers null, splice-site, deletion, duplication, and initiation-codon variants.	cspec pvs1_variant_assessment vcep_pvs1_decisiontree_pten
PS1	Not assessed	Not assessed: no verified previously established pathogenic p.Phe257Leu or qualifying pathogenic splicing comparator was available for c.771C>A.	cspec pm5_candidates clinvar
PS2	Not assessed	Not assessed: no documented proband de novo observation, confirmed maternity and paternity, or absence of family history is available.	cspec
PS3	Met	Met at Moderate: PTEN F257L has high-confidence Cum_score -2.055963973, below the VCEP PS3 threshold of ≤ -1.11.	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no VCEP-required case-control statistics or proband phenotype-specificity score is available for this variant.	cspec
PM1	Not met	Not met: p.Phe257 is outside all three VCEP catalytic intervals (90–94, 123–130, and 166–168), and no statistically significant hotspot was identified.	cspec
PM2	Met	Met, Supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PTEN PM2 threshold of less than 0.00001 (0.001%) allele frequency.	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: p.(Phe257Leu) is a missense substitution and does not create the in-frame length change or stop-loss event required by the PTEN PM4 rule.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: no qualifying pathogenic or likely pathogenic different missense variant at PTEN residue 257 was available for the required BLOSUM62 comparison.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no documented presumed de novo proband, disease status, family-history assessment, or independent observation count is available.	cspec
PP1	Not assessed	Not assessed: no affected relatives, segregation results, or meiosis count are documented for comparison with the 3-meiosis minimum.	cspec
PP2	Not assessed	Not assessed: the variant is missense, but VCEP-governed evidence establishing both required PTEN gene-level conditions is unavailable.	cspec
PP3	Not met	Not met: the VCEP missense PP3 pathway requires REVEL > 0.7, but this variant's REVEL score is 0.631.	cspec revel
PP4	N/A	Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 rather than allowing independent PP4 use.	cspec
PP5	N/A	Not applicable: the PTEN VCEP explicitly prohibits use of PP5 regardless of the available ClinVar citation trail.	cspec
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the PTEN BA1 threshold of 0.00056 (0.056%).	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: no allele frequency was observed in gnomAD v2.1 or v4.1, below the PTEN BS1 Supporting lower bound of 0.0000043 (0.00043%).	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports no variant observation and provides no qualifying healthy or PHTS-unaffected homozygous individual under the PTEN BS2 rule.	cspec gnomad_v2 gnomad_v4
BS3	Not met	Not met: PTEN F257L has high-confidence Cum_score -2.055963973, not the VCEP BS3 requirement of phosphatase activity >0.	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no affected relatives lacking the variant or family-level non-segregation analysis is documented.	cspec
BP1	N/A	Not applicable: the ClinGen PTEN VCEP specification explicitly marks BP1 as not applicable.	cspec
BP2	Not assessed	Not assessed: no documented trans observation or three cis/phase-unknown observations with different pathogenic/likely pathogenic PTEN variants were available.	cspec
BP3	N/A	Not applicable: the PTEN VCEP explicitly marks BP3 as Not Applicable for this framework.	cspec
BP4	Not met	Not met: the VCEP missense BP4 pathway requires REVEL < 0.5, but this variant's REVEL score is 0.631.	cspec revel
BP5	Not assessed	Not assessed: no qualifying alternate molecular diagnosis, two cases, penetrance evidence, or non-overlapping history is documented.	cspec
BP6	N/A	Not applicable: the PTEN VCEP explicitly prohibits use of BP6 under its specification.	cspec
BP7	N/A	Not applicable: this variant is missense (p.Phe257Leu), whereas BP7 is limited to synonymous or intronic variants at or beyond +7/-21.	cspec

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