Variant classification summary

NM_000314.8:c.304A>T

PTEN · NP_000305.3:p.(Lys102Ter) · NM_000314.8

GRCh37: chr10:89692820 A>T · GRCh38: chr10:87933063 A>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.(Lys102Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTEN NM_000314.8:c.304A>T (p.Lys102Ter, p.K102*) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic by one clinical laboratory.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2_Supporting threshold of 0.001% and supports rarity in population databases.

3

This is an early truncating PTEN variant, and under the PTEN-specific PVS1 decision tree a stop codon at codon 102 is upstream of the p.D375 (c.1121) threshold used for full-strength PVS1.

4

SpliceAI predicts no significant splice effect with a maximum delta score of 0.04, and a BayesDel score of 0.652534 is available; however, the PTEN VCEP PP3/BP4 computational rules are specified for missense or defined splicing variants and were not applied to this nonsense variant.

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.304A>T (p.Lys102Ter/p.K102*), in the biologically relevant PTEN transcript. Under the PTEN-specific PVS1 decision tree, a stop codon at or 5' to p.D375 (c.1121) is assigned PVS1; this stop at codon 102 is well upstream of that threshold and is consistent with a loss-of-function allele.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_decisiontree_pten
PS1	Not met	No previously established pathogenic variant producing the same amino acid change by a different nucleotide change was identified in the available evidence, so PS1 is not met.	clinvar cspec
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified in the available evidence, so PS2 was not assessed.	clinvar cspec
PS3	Not assessed	No well-established functional study specific to this variant was identified that demonstrates a damaging effect suitable for PTEN PS3. The PTEN VCEP functional assay file highlighted for PS3/BS3 is a missense phosphatase assay and is not directly applicable to this nonsense variant.	cspec vcep_mmc2
PS4	Not assessed	The available evidence does not establish a confirmed count of unrelated affected probands or a case-control enrichment for this variant, so PS4 was not assessed.	clinvar cspec
PM1	Not met	This variant is at codon 102, which is outside the PTEN catalytic motif residues defined for PM1 (90-94, 123-130, and 166-168), and no statistically significant hotspot evidence was identified for this site. PM1 is not met.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. Under the PTEN VCEP PM2 rule, absence or an allele frequency below 0.001% supports PM2_Supporting; the observed frequency is 0, which is below that threshold.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the PTEN framework for this autosomal dominant condition.	cspec
PM4	N/A	PM4 applies to in-frame protein length changes or stop-loss variants. This variant is a nonsense change and is assessed under PVS1 rather than PM4.	cspec
PM5	N/A	PM5 is a missense criterion and does not apply to this nonsense variant.	cspec
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified in the available evidence, so PM6 was not assessed.	clinvar cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.	clinvar cspec
PP2	N/A	PP2 is a missense criterion and does not apply to this nonsense variant.	cspec
PP3	N/A	PTEN PP3 is specified for missense variants with REVEL >0.7 or for splicing variants with concordant splice predictions. This variant is a nonsense change, REVEL was not available, SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, and the available BayesDel score of 0.652534 is not used by the PTEN VCEP PP3 rule for this variant type. PP3 is not applicable.	cspec spliceai bayesdel
PP4	N/A	PP4 is not applicable in the PTEN VCEP framework because phenotype specificity is incorporated into PS4.	cspec
PP5	N/A	PP5 is not applicable in the PTEN VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its allele frequency is well below the PTEN BA1 threshold of >0.056%. BA1 is not met.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its allele frequency is below the PTEN BS1 thresholds of 0.00043% for supporting and 0.0043% for strong evidence. BS1 is not met.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No homozygous observations in healthy or PTEN hamartoma tumor syndrome-unaffected individuals were identified in the available evidence, so BS2 was not assessed.	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 functional assay file indexed for BS3 is a missense phosphatase assay and is not directly applicable to this nonsense variant.	cspec vcep_mmc2
BS4	Not assessed	No lack-of-segregation evidence was identified for this variant, so BS4 was not assessed.	clinvar cspec
BP1	N/A	BP1 is not applicable in the PTEN VCEP framework.	cspec
BP2	Not assessed	No evidence was identified that this variant has been observed in trans with a pathogenic PTEN variant or in cis/phase unknown with multiple pathogenic PTEN variants, so BP2 was not assessed.	cspec clinvar
BP3	N/A	BP3 is not applicable in the PTEN VCEP framework.	cspec
BP4	N/A	PTEN BP4 is specified for missense variants with REVEL <0.5 or for synonymous/intronic splicing variants with benign splice predictions. This variant is a nonsense change. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, BP4 is not the applicable criterion for this variant type.	cspec spliceai bayesdel
BP5	Not assessed	No alternate molecular diagnosis with a non-overlapping phenotype was identified in the available evidence, so BP5 was not assessed.	cspec
BP6	N/A	BP6 is not applicable in the PTEN VCEP framework.	cspec
BP7	N/A	BP7 applies to synonymous or deep intronic variants with no predicted splicing effect. This variant is a nonsense coding change, so BP7 is not applicable.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.