Variant classification summary

NM_000314.8:c.521del

PTEN · NP_000305.3:p.(Tyr174LeufsTer9) · NM_000314.8

GRCh37: chr10:89711902 TA>T · GRCh38: chr10:87952145 TA>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.(Tyr174LeufsTer9)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: the frameshift is 5′ of PTEN p.D375/c.1121 and meets the Expert Panel's nonsense-mediated-decay rule.

2

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1, below the PTEN population-frequency threshold.

Final determination: PTEN Expert Panel Rule20 classifies a variant as Likely Pathogenic when one Pathogenic.Very Strong criterion and one Pathogenic.Supporting criterion are met; here these are PVS1 very strong and PM2 supporting.

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 at very strong strength: NM_000314.8:c.521del causes p.(Tyr174LeufsTer9), a frameshift 5′ of p.D375/c.1121, meeting the PTEN VCEP NMD branch.	cspec vcep_pvs1_decisiontree_pten
PS1	N/A	Not applicable: c.521del is a frameshift producing p.(Tyr174LeufsTer9), not a missense or splice-site variant eligible for the PTEN VCEP PS1 rule.	cspec
PS2	Not assessed	Not assessed: no proband diagnosis, parental testing, maternity/paternity confirmation, or family-history data are documented.	cspec
PS3	Not assessed	Not assessed: the PTEN VCEP assay table is restricted to missense variants, and no c.521del or p.Tyr174LeufsTer9 entry was found.	cspec vcep_mmc2 PMID:11237521 PMID:17218262
PS4	Not assessed	Not assessed: no case-control enrichment, confidence interval, or variant-specific phenotype score is available for applying the PTEN PS4 thresholds.	cspec
PM1	Not assessed	Not assessed: PTEN Y174 is reported as a hotspot, but the partial hotspot source lacks a valid source_registry key required to audit PM1 evidence.	cspec
PM2	Met	Met, supporting: the variant is absent (observed allele frequency 0) in gnomAD v2.1 and v4.1, below the PTEN PM2 threshold of 0.00001.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP explicitly excludes PM3 for this autosomal dominant disorder.	cspec
PM4	N/A	Not applicable: the PTEN VCEP PM4 rule covers in-frame indels or stop-loss variants, whereas c.521del is a frameshift.	cspec
PM5	N/A	Not applicable: c.521del is a frameshift producing p.(Tyr174LeufsTer9), whereas PM5 requires a missense change and a same-residue missense comparator.	cspec
PM6	Not assessed	Not assessed: no qualifying assumed de novo observation, proband disease documentation, family history, or count of independent observations is available.	cspec
PP1	Not assessed	Not assessed: no affected relatives, co-segregation observations, family structure, or meiosis count are documented.	cspec
PP2	N/A	Not applicable: PP2 requires a missense variant, while c.521del is a PTEN frameshift producing p.(Tyr174LeufsTer9).	cspec
PP3	N/A	Not applicable: NM_000314.8:c.521del is a frameshift variant, outside PP3's missense or intronic/splice-region computational-evidence scope.	cspec pvs1_variant_assessment
PP4	N/A	Not applicable: the PTEN Expert Panel incorporates phenotype specificity into PS4 and explicitly excludes PP4.	cspec
PP5	N/A	Not applicable: ClinVar has no exact-variant expert-panel pathogenic classification, and the PTEN framework excludes PP5.	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 (0.056%).	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD, so its frequency does not fall within the PTEN BS1 interval of 0.0000043–0.00056.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no confirmed homozygous observation in a healthy or PHTS-unaffected individual is available for this absent variant.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no applicable benign functional assay was found, and the governing PTEN table contains no entry for this frameshift variant.	cspec vcep_mmc2 PMID:11237521 PMID:17218262
BS4	Not assessed	Not assessed: no non-segregating affected relatives, family segregation results, or number of families are documented.	cspec
BP1	N/A	Not applicable: the PTEN VCEP marks BP1 as not applicable, and c.521del is a frameshift producing p.(Tyr174LeufsTer9).	cspec
BP2	Not assessed	Not assessed: no second pathogenic PTEN variant or cis/trans phase observation is documented for the required BP2 evidence.	cspec
BP3	N/A	Not applicable: the PTEN VCEP lists BP3 as not applicable, and c.521del is a frameshift rather than an in-frame repeat-region deletion.	cspec
BP4	N/A	Not applicable: NM_000314.8:c.521del is a frameshift variant, outside BP4's missense or intronic/splice-region computational-evidence scope.	cspec pvs1_variant_assessment
BP5	Not assessed	Not assessed: no two qualifying cases with a highly penetrant alternate diagnosis and non-overlapping PTEN history are documented.	cspec
BP6	N/A	Not applicable: the PTEN Expert Panel excludes BP6 and ClinVar has no exact-variant expert-panel benign classification.	cspec clinvar
BP7	N/A	Not applicable: NM_000314.8:c.521del is a frameshift variant, not a synonymous variant eligible for BP7.	cspec pvs1_variant_assessment

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