Variant classification summary

NM_000314.8:c.-326_-324delinsCCC

PTEN · NP_000305.3:p.? · NM_000314.8

GRCh37: chr10:89623901 GCG>CCC · GRCh38: chr10:87864144 GCG>CCC

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 supports the classification at Supporting strength because the variant is absent from gnomAD v2.1 and v4.1.

Final determination: Because only PM2 at Supporting strength is applied, no PTEN Expert Panel pathogenic, likely pathogenic, benign, or likely benign combination rule is satisfied, so the classification 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: the exon 1 5' UTR substitutions have predicted protein consequence p.(=) and are not a VCEP-defined null, splice-site, deletion, duplication, or initiation-codon variant.	cspec vcep_pvs1_decisiontree_pten
PS1	N/A	Not applicable: the upstream-of-CDS variant has protein consequence p.? and is neither a same-amino-acid nor pathogenic splice-position change.	cspec
PS2	Not assessed	Not assessed: no proband de novo observation, parental testing, maternity/paternity confirmation, disease phenotype, or family-history information is available.	cspec
PS3	Not assessed	Not assessed: the governing mmc2.xlsx search found no c.-326_-324delinsCCC or p.? entry and no case-specific damaging functional result is available.	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no case-control statistics or qualifying proband phenotype-specificity scores are available to compare with the PTEN VCEP PS4 thresholds.	cspec
PM1	N/A	Not applicable: the upstream-of-CDS variant has no translated residue and cannot occupy PTEN catalytic-motif residues 90-94, 123-130, or 166-168.	cspec
PM2	Met	Met at Supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the VCEP requirement for <0.00001 (0.001%) allele frequency.	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 exon 1 5' UTR substitutions have predicted protein consequence p.(=) and produce no protein length change required by the PM4 rule.	cspec
PM5	N/A	Not applicable: the upstream-of-CDS variant is noncoding with protein consequence p.? and is not a missense change at an amino-acid residue.	cspec
PM6	Not assessed	Not assessed: no de novo observations, proband disease phenotype, family history, or parental testing information is available to evaluate PM6 thresholds.	cspec
PP1	Not assessed	Not assessed: no affected relatives, segregation observations, family structure, or meiosis count is available for evaluating PP1.	cspec
PP2	N/A	Not applicable: PP2 requires a missense variant, whereas this upstream-of-CDS variant has protein consequence p.?.	cspec
PP3	Not assessed	Not assessed: the PTEN rule requires concordance of SpliceAl and VarSeak for splicing variants, but only SpliceAI (maximum delta 0.015) is available.	cspec spliceai
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 prohibits use of PP5 under the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding 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, so its frequency does not fall within either 0.0000043–0.00056 BS1 interval.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports absence and provides no confirmed or unconfirmed homozygous observations in healthy or PHTS-unaffected individuals.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: mmc2.xlsx contains no matching c.-326_-324delinsCCC or p.? entry and provides no variant-specific phosphatase activity >0 value.	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no affected-family-member genotypes or segregation results are available to evaluate lack of segregation in one or more families.	cspec
BP1	N/A	Not applicable: the ClinGen PTEN VCEP explicitly marks BP1 as Not Applicable.	cspec
BP2	Not assessed	Not assessed: no affected-proband, phase, or cis/trans observations pairing this variant with a pathogenic or likely pathogenic PTEN variant are available.	cspec
BP3	N/A	Not applicable: the PTEN VCEP explicitly excludes BP3 for PTEN, regardless of repeat-region or protein-consequence context.	cspec
BP4	Not assessed	Not assessed: the PTEN rule requires concordance of SpliceAl and VarSeak for splicing variants, but only SpliceAI (maximum delta 0.015) is available.	cspec spliceai
BP5	Not assessed	Not assessed: no two qualifying cases with a highly penetrant alternate disorder and non-overlapping PTEN history are documented.	cspec
BP6	N/A	Not applicable: the PTEN VCEP prohibits use of BP6 under the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	N/A	Not applicable: c.-326_-324delinsCCC is a 5'-UTR variant, not a synonymous or intronic variant at or beyond +7/-21.	cspec

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.