Variant classification summary

NM_000314.8:c.69_73del

PTEN · NP_000305.3:p.(Leu23PhefsTer19) · NM_000314.8

GRCh37: chr10:89624293 TTAGAC>T · GRCh38: chr10:87864536 TTAGAC>T

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.(Leu23PhefsTer19)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: the exon 1 frameshift is 5' to the PTEN VCEP's c.1121 NMD threshold.

2

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

Final determination: Under Rule20 of the ClinGen PTEN Expert Panel Version 3.2 framework, one Pathogenic Very Strong criterion plus one Pathogenic Supporting criterion yields Likely Pathogenic.

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, very strong: the exon 1 frameshift at c.69_73del is 5' to the VCEP's c.1121 NMD threshold in NM_000314.8.	cspec vcep_pvs1_decisiontree_pten pvs1_variant_assessment
PS1	N/A	Not applicable: c.69_73del is a frameshift producing p.(Leu23PhefsTer19), not a same-amino-acid missense or intronic splice-site substitution.	cspec
PS2	Not assessed	Not assessed: no proband-level de novo observation with confirmed maternity and paternity and no family history is documented.	cspec
PS3	N/A	Not applicable: the governing mmc2 assay file covers missense variants, while this variant is a frameshift and has no exact functional-assay entry.	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no case-control counts, odds ratio, confidence interval, or PTEN phenotype-specificity scores are available to evaluate the VCEP PS4 rule.	cspec
PM1	Not met	Not met: residue 23 is outside all VCEP-approved catalytic motifs, which are limited to residues 90-94, 123-130, and 166-168.	cspec hotspots
PM2	Met	Met, Supporting: the variant is absent from gnomAD v2.1 and v4.1, meeting the PTEN PM2 threshold below 0.00001 (0.001%).	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP explicitly designates PM3 as not applicable to PTEN.	cspec
PM4	N/A	Not applicable: PM4 is limited to in-frame indels or stop-loss/protein-extension changes, whereas c.69_73del is a frameshift.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: PM5 requires a missense change with a BLOSUM62 comparison, whereas this variant is a frameshift at c.69_73del.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no affected proband with an assumed or presumed de novo occurrence and documented family-history or parental-confirmation status is available.	cspec
PP1	Not assessed	Not assessed: zero documented family meioses are available to evaluate the VCEP thresholds of 3–4, 5–6, or at least 7 meioses.	cspec
PP2	N/A	Not applicable: PP2 is restricted to missense variants, while c.69_73del causes the frameshift p.(Leu23PhefsTer19).	cspec
PP3	N/A	Not applicable: PP3 names splicing or missense variants, whereas NM_000314.8:c.69_73del is a frameshift variant.	cspec
PP4	N/A	Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 Use 2 and explicitly excludes independent PP4 application.	cspec
PP5	N/A	Not applicable: the PTEN VCEP states that PP5 is not for use under the VCEP Review Committee recommendation.	cspec
BA1	Not met	Not met: gnomAD v2.1 and v4.1 report the variant absent, not a filtering allele frequency greater than 0.00056 (0.056%).	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 report absence, with no allele frequency in the PTEN BS1 range of 0.0000043 to 0.00056.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no reported homozygous healthy individual.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the governing mmc2 assay file covers missense variants, while this variant is a frameshift and has no exact functional-assay entry.	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no affected-family segregation results are documented for the one-family or two-family VCEP BS4 thresholds.	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 trans observation or at least three cis/unknown-phase observations with different pathogenic or likely pathogenic PTEN variants.	cspec
BP3	N/A	Not applicable: the PTEN VCEP CSPEC explicitly marks BP3 as Not Applicable.	cspec
BP4	N/A	Not applicable: BP4 is limited to splicing or missense variants, while this variant is a frameshift despite a SpliceAI max delta of 0.092.	cspec
BP5	Not assessed	Not assessed: no two qualifying cases with a highly penetrant alternate diagnosis and non-overlapping PTEN personal or family history are documented.	cspec
BP6	N/A	Not applicable: the PTEN VCEP states that BP6 is not for use under the VCEP Review Committee recommendation.	cspec
BP7	N/A	Not applicable: BP7 requires a synonymous or intronic variant at or beyond +7/-21, but this variant is an exon 1 frameshift.	cspec

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