Variant classification summary

NM_000314.8:c.419T>A

PTEN · NP_000305.3:p.(Leu140Ter) · NM_000314.8

GRCh37: chr10:89692935 T>A · GRCh38: chr10:87933178 T>A

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.(Leu140Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: the exon-5 nonsense stop at c.419 is 5' to the PTEN VCEP's c.1121 NMD cutoff.

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 a Likely Pathogenic classification.

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-5 nonsense stop at c.419 is 5' to the PTEN VCEP's c.1121 NMD cutoff in NM_000314.8.	cspec vcep_pvs1_decisiontree_pten pvs1_variant_assessment
PS1	Not assessed	Not assessed: no previously established pathogenic comparator with the same amino acid change or a qualifying pathogenic splicing comparator at c.419 was available.	cspec clinvar
PS2	Not assessed	Not assessed: no documented proband-level de novo observation with confirmed maternity and paternity or the VCEP-required observation count.	cspec
PS3	N/A	Not applicable: the governing PTEN functional-assay rule is limited to missense variants, whereas c.419T>A produces the nonsense change p.(Leu140Ter).	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no VCEP specificity score or affected-versus-control prevalence data is available for PTEN c.419T>A.	cspec PMID:24493721 PMID:34012068 PMID:11237521 PMID:17218262
PM1	Not met	Not met: residue 140 is outside all VCEP-defined PM1 regions, 90-94, 123-130, and 166-168, and no separate hotspot route is specified.	cspec hotspots
PM2	Met	Met at Supporting: the variant is absent from gnomAD v2.1 and v4.1, giving allele frequency 0 below the <0.00001 PM2 threshold.	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: c.419T>A is a premature-stop nonsense variant, whereas PTEN PM4 covers in-frame indels, stop-loss variants, and protein extension.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: the variant is nonsense, but the PTEN PM5 rule requires an interrogated missense change and a different pathogenic or likely pathogenic missense change.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no documented presumed de novo proband, parental-confirmation status, family-history status, or VCEP-required observation count.	cspec
PP1	Not assessed	Not assessed: no documented affected relatives or co-segregating meioses are available to meet the VCEP's minimum of 3 meioses.	cspec
PP2	N/A	Not applicable: PP2 is restricted to missense variants, whereas this variant is the nonsense change p.(Leu140Ter).	cspec
PP3	N/A	Not applicable: PP3 covers synonymous/intronic splice-impact variants or missense variants with REVEL >0.7, whereas this variant is nonsense.	cspec
PP4	N/A	Not applicable: the PTEN VCEP explicitly designates PP4 as Not Applicable.	cspec
PP5	N/A	Not applicable: the PTEN VCEP explicitly designates PP5 as Not Applicable, regardless of the single-submitter ClinVar classification.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, corresponding to allele frequency 0, below the >0.00056 BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 report the variant absent, with allele frequency 0 below the BS1 Supporting lower bound of 0.0000043.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports no variant observations, so there is no homozygous healthy-individual observation or confirmation data for the BS2 rule.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the governing PTEN functional-assay rule is limited to missense variants, whereas c.419T>A produces the nonsense change p.(Leu140Ter).	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no documented affected-family non-segregation observation is available for the VCEP's one-family or two-family thresholds.	cspec
BP1	N/A	Not applicable: the ClinGen PTEN VCEP marks BP1 as Not Applicable.	cspec
BP2	Not assessed	Not assessed: no documented trans observation or three qualifying cis/phase-unknown observations with different pathogenic PTEN variants are available.	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 covers synonymous/intronic no-impact splice predictions or missense variants with REVEL <0.5, not nonsense variants.	cspec
BP5	Not assessed	Not assessed: no alternate highly penetrant molecular diagnosis and non-overlapping personal/family history are documented for this case.	cspec
BP6	N/A	Not applicable: the PTEN VCEP explicitly designates BP6 as Not Applicable.	cspec clinvar
BP7	N/A	Not applicable: BP7 is restricted to synonymous or intronic variants at or beyond +7/-21, whereas this variant is nonsense.	cspec

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