Variant classification summary

NM_000314.8:c.276_277insG

PTEN · NP_000305.3:p.(His93AlafsTer2) · NM_000314.8

GRCh37: chr10:89692792 C>CG · GRCh38: chr10:87933035 C>CG

Gene: PTEN Transcript: NM_000314.8

Final call

Pathogenic

PVS1 very strong PM1 moderate PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(His93AlafsTer2)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 is very strong because the frameshift truncates PTEN at His93 before the VCEP NMD threshold.

2

Pathogenic: PM1 is moderate because the frameshift begins within the PTEN VCEP critical interval at residues 90-94.

3

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

Final determination: Under Rule3 of the ClinGen PTEN Expert Panel Version 3.2 framework, one very strong pathogenic criterion, one moderate pathogenic criterion, and one supporting pathogenic criterion combine to yield 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 frameshift truncates PTEN at His93, well before the VCEP p.D375 (c.1121) NMD threshold.	cspec vcep_pvs1_decisiontree_pten
PS1	N/A	Not applicable: the variant is a frameshift, p.(H93Afs*2), rather than a missense amino-acid substitution required for same-amino-acid PS1.	cspec
PS2	Not assessed	Not assessed: no documented parental testing establishes a confirmed de novo occurrence for the proband.	cspec
PS3	Not assessed	Not assessed: the PTEN VCEP assay table contains no entry for this frameshift, and its <= -1.11 PS3_Moderate threshold applies only to exact high-confidence missense results.	cspec vcep_mmc2 PMID:11237521 PMID:17218262
PS4	Not assessed	Not assessed: no case-control enrichment statistics or PTEN phenotype-specific proband score is available to compare with the VCEP PS4 thresholds.	cspec
PM1	Met	Met, moderate: the frameshift starts at His93, within the PTEN VCEP critical interval 90-94, and H93 is recorded as a statistically significant hotspot.	cspec
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PTEN PM2 requirement of allele frequency below 0.00001.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN Expert Panel specification explicitly designates PM3 as not applicable for this autosomal-dominant disorder.	cspec
PM4	N/A	Not applicable: this insertion is a frameshift with premature termination, not an in-frame length change or stop-loss extension covered by PTEN PM4.	cspec
PM5	N/A	Not applicable: PM5 requires a missense change and BLOSUM62 comparison, whereas this variant is the frameshift p.(H93Afs*2).	cspec pm5_candidates
PM6	Not assessed	Not assessed: no documented presumed de novo observation in an affected proband is available for PM6.	cspec
PP1	Not assessed	Not assessed: no affected relatives or informative meioses are documented to evaluate cosegregation.	cspec
PP2	N/A	Not applicable: PP2 is restricted to missense variants, while this variant is the frameshift p.(H93Afs*2).	cspec
PP3	N/A	Not applicable: NM_000314.8:c.276_277insG is a frameshift variant, outside PP3 scope for missense or splice-region/intronic computational evidence.	cspec
PP4	N/A	Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 Use 2 and explicitly marks PP4 as not applicable.	cspec
PP5	N/A	Not applicable: the PTEN VCEP does not use PP5, and this exact variant has no ClinVar Expert Panel pathogenic or likely pathogenic classification.	cspec clinvar
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.	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 reach the PTEN BS1 lower threshold of 0.000043.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: no homozygous observation in a healthy or PHTS-unaffected individual is reported, and the variant is absent from gnomAD v2.1 and v4.1.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific benign assay result was found, and the VCEP's >0 BS3 threshold applies to an exact missense assay entry absent for this frameshift.	cspec vcep_mmc2 PMID:11237521 PMID:17218262
BS4	Not assessed	Not assessed: no affected relatives with documented non-segregation are available to support BS4.	cspec
BP1	N/A	Not applicable: the PTEN VCEP marks BP1 not applicable, and this variant is a truncating frameshift rather than a missense change.	cspec
BP2	Not assessed	Not assessed: no documented cis, trans, or phase-unknown observation with a pathogenic or likely pathogenic PTEN variant is available.	cspec
BP3	N/A	Not applicable: PTEN VCEP marks BP3 not applicable, and this variant is a truncating frameshift rather than an in-frame repeat-region indel.	cspec
BP4	N/A	Not applicable: NM_000314.8:c.276_277insG is a frameshift variant, outside BP4 scope for missense or splice-region/intronic computational evidence.	cspec
BP5	Not assessed	Not assessed: two qualifying cases with a highly penetrant alternate diagnosis and non-overlapping PTEN history are not documented.	cspec
BP6	N/A	Not applicable: the PTEN VCEP does not use BP6, and this exact variant has no ClinVar Expert Panel benign or likely benign classification.	cspec clinvar
BP7	N/A	Not applicable: NM_000314.8:c.276_277insG is a frameshift variant, not a synonymous variant eligible for BP7.	cspec

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