Variant classification summary

NM_000314.8:c.514_515del

PTEN · NP_000305.3:p.(Arg172AlafsTer7) · NM_000314.8

GRCh37: chr10:89711893 CAG>C · GRCh38: chr10:87952136 CAG>C

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.(Arg172AlafsTer7)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PVS1 very strong reflects the exon 6 frameshift's predicted loss of function through premature truncation.

2

Likely Pathogenic: PM2 supporting reflects the variant's absence 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 6 frameshift introduces a premature stop at p.Arg172, well 5' of the PTEN NMD threshold p.D375 (c.1121).	cspec vcep_pvs1_decisiontree_pten pvs1_variant_assessment
PS1	N/A	Not applicable: the variant is a frameshift, p.(Arg172AlafsTer7), not an amino-acid substitution eligible for same-amino-acid PS1.	cspec
PS2	Not assessed	Not assessed: no documented proband phenotype, parental testing, family-history status, or confirmed de novo observation is available.	cspec
PS3	Not assessed	Not assessed: mmc2.xlsx contains no exact c.514_515del, Arg172AlafsTer7, or R172Afs*7 assay row for the required functional evidence.	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no verified case-control counts, odds ratio, confidence interval, or PTEN phenotype-specificity score is available for this exact variant.	cspec gnomad_v2 gnomad_v4 gnomad_canada PMID:9467011 PMID:21194675 PMID:23788249 PMID:25190698
PM1	Not met	Not met: the frameshift starts at residue 172, outside the VCEP PM1 catalytic-motif ranges 90-94, 123-130, and 166-168.	cspec hotspots
PM2	Met	Met at supporting strength: The variant is absent from gnomAD v2.1 and v4.1, below the VCEP PM2 threshold of <0.00001 allele frequency.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP explicitly excludes PM3, regardless of available phase or affected-proband observations.	cspec
PM4	N/A	Not applicable: PM4 covers in-frame length changes or stop-loss variants, whereas this variant is a frameshift at c.514_515del.	cspec
PM5	N/A	Not applicable: PM5 requires a missense change, whereas this variant is the frameshift p.(Arg172AlafsTer7).	cspec
PM6	Not assessed	Not assessed: no assumed de novo observation, affected-proband evidence, family-history status, or qualifying observation count is documented.	cspec
PP1	Not assessed	Not assessed: zero informative meioses or affected relatives carrying this exact variant are documented, so no PP1 threshold can be reached.	cspec PMID:9467011
PP2	N/A	Not applicable: PP2 is limited to missense variants, while this variant is the frameshift p.(Arg172AlafsTer7).	cspec
PP3	N/A	Not applicable: the PTEN VCEP PP3 rule covers splicing or missense variants, whereas this variant is a frameshift at c.514_515del.	cspec
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 PP5 use, regardless of the available ClinVar pathogenic submission or literature classifications.	cspec clinvar
BA1	Not met	Not met: The variant is absent from gnomAD v2.1 and v4.1, giving an observed allele frequency of 0 rather than >0.00056.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: The variant is absent from gnomAD v2.1 and v4.1, so no allele frequency falls within the VCEP BS1 range of 0.000043–0.00056.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: Available gnomAD records show no homozygous healthy or PHTS-unaffected individual, so the VCEP BS2 requirement cannot be evaluated.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: mmc2.xlsx contains no exact c.514_515del, Arg172AlafsTer7, or R172Afs*7 assay row showing no damaging effect.	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no affected family member tested negative for this exact variant and no family-level non-segregation analysis is documented.	cspec
BP1	N/A	Not applicable: the PTEN VCEP explicitly marks BP1 as Not Applicable.	cspec
BP2	Not assessed	Not assessed: no qualifying trans observation, phase relationship, or three-observation cis/unknown-phase series with different pathogenic PTEN variants is documented.	cspec
BP3	N/A	Not applicable: the PTEN VCEP explicitly states that BP3 is not applicable to PTEN.	cspec
BP4	N/A	Not applicable: BP4 cannot assess no gene-product impact for this exon 6 frameshift, even if a splice predictor shows no splice effect.	cspec
BP5	Not assessed	Not assessed: no two qualifying cases with a highly penetrant alternate disorder and non-overlapping PTEN personal or family histories are documented.	cspec
BP6	N/A	Not applicable: the PTEN VCEP explicitly prohibits BP6 use under its governing specifications.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous or sufficiently distant intronic variants, but c.514_515del is an exonic frameshift.	cspec

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