Variant classification summary

NM_000314.8:c.416T>G

PTEN · NP_000305.3:p.(Leu139Ter) · NM_000314.8

GRCh37: chr10:89692932 T>G · GRCh38: chr10:87933175 T>G

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.(Leu139Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTEN c.416T>G (p.(Leu139Ter)) variant has been observed in somatic cancers (COSMIC COSV64297098, n=6) and has been reported in ClinVar as pathogenic by a single submitter.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the PTEN VCEP PM2_Supporting rarity threshold of less than 0.001% allele frequency.

3

This variant introduces a premature stop codon at Leu139, and under the PTEN-specific PVS1 decision tree truncating variants at or 5' to p.D375 in transcript NM_000314.8 are assigned PVS1; SpliceAI predicts no significant splice effect with a maximum delta score of 0.01.

Final determination: Rule20 in the Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as 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	This variant is a nonsense change, NM_000314.8:c.416T>G (p.(Leu139Ter)), predicted to truncate PTEN early in the coding sequence. Under the PTEN-specific PVS1 decision tree, truncating variants at or 5' to p.D375 (c.1121) in biologically relevant transcript NM_000314.8 are assigned PVS1, and Leu139Ter is upstream of that threshold.	cspec vcep_pvs1_decisiontree_pten pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No prior pathogenic variant with a different nucleotide change producing the same amino acid change was identified in the reviewed evidence, so PS1 was not applied.	clinvar cspec
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 was not applied.	cspec
PS3	Not assessed	No variant-specific functional study meeting the PTEN VCEP PS3 rules was identified for this nonsense variant. The PTEN VCEP phosphatase activity framework in Mighell et al. applies to missense variants, and no RNA or other assay demonstrating an abnormal effect specific to this variant was available.	cspec vcep_mmc2
PS4	Not assessed	This variant has been reported in ClinVar and in somatic cancers in COSMIC, but no countable germline proband data or case-control enrichment meeting the PTEN VCEP PS4 rules were identified. The available observations are therefore insufficient to apply PS4.	clinvar cspec
PM1	Not met	This variant is not located in a PTEN catalytic motif defined for PM1. PTEN VCEP PM1 is limited to residues 90-94, 123-130, and 166-168, and Cancer Hotspots did not identify L139 as a statistically significant hotspot.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. This is below the PTEN VCEP PM2 threshold of <0.00001 (0.001%) allele frequency and supports PM2_Supporting.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the PTEN VCEP framework for this autosomal dominant PTEN-related context.	cspec
PM4	N/A	This variant is a nonsense change rather than an in-frame insertion/deletion or stop-loss variant, so PM4 does not apply.	cspec
PM5	N/A	PM5 was not applied because the PTEN VCEP uses classic same-residue missense logic, and this variant is a nonsense change rather than a missense variant.	cspec pm5_candidates
PM6	Not assessed	No presumed de novo observation without parental confirmation was identified for this variant, so PM6 was not applied.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not applied.	cspec
PP2	N/A	PP2 is a missense criterion and was not applied because this variant is a nonsense change.	cspec
PP3	N/A	Available computational data include SpliceAI max delta score 0.01, no REVEL score, and BayesDel 0.652534, but the PTEN VCEP PP3 rule is defined for missense variants with REVEL >0.7 or for splicing variants with concordant splice prediction. Because this variant is an early nonsense change rather than a missense or splice-region variant, PP3 was not applied.	cspec spliceai bayesdel
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the PTEN VCEP BA1 threshold of >0.00056 (0.056%).	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the PTEN VCEP BS1 thresholds of 0.0000043-0.00056 allele frequency.	cspec gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observation in a healthy or PTEN hamartoma tumor syndrome-unaffected individual was identified for this variant, so BS2 was not applied.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study showing no damaging effect for this variant was identified. The PTEN VCEP benign phosphatase activity framework in Mighell et al. applies to missense variants, and no variant-specific benign functional evidence was available for this nonsense variant.	cspec vcep_mmc2
BS4	Not assessed	No lack-of-segregation evidence was identified for this variant, so BS4 was not applied.	cspec
BP1	N/A	BP1 is not applicable in the PTEN VCEP framework.	cspec
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic PTEN variant or in cis/phase unknown with multiple pathogenic PTEN variants, so BP2 was not applied.	cspec
BP3	N/A	BP3 is not applicable in the PTEN VCEP framework.	cspec
BP4	N/A	Available computational data include SpliceAI max delta score 0.01, no REVEL score, and BayesDel 0.652534, but the PTEN VCEP BP4 rule is defined for missense variants with REVEL <0.5 or for qualifying splicing variants with concordant benign splice prediction. Because this variant is a nonsense change rather than a missense or intronic/synonymous splicing candidate, BP4 was not applied.	cspec spliceai bayesdel
BP5	Not assessed	No alternate highly penetrant molecular explanation with a non-overlapping phenotype was identified, so BP5 was not applied.	cspec
BP6	N/A	BP6 is not applicable in the PTEN VCEP framework.	cspec
BP7	N/A	BP7 applies to synonymous or qualifying intronic variants, but this variant is a nonsense coding change, so BP7 does not apply.	cspec
PP4	N/A	PP4 is not applicable in the PTEN VCEP framework because phenotype specificity is incorporated into PS4 scoring.	cspec
PP5	N/A	PP5 is not applicable in the PTEN VCEP framework.	cspec

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