Variant classification summary

NM_000314.8:c.418_430del

PTEN · NP_000305.3:p.(Leu140AsnfsTer3) · NM_000314.8

GRCh37: chr10:89692932 TATTACATCGGGGC>T · GRCh38: chr10:87933175 TATTACATCGGGGC>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.(Leu140AsnfsTer3)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTEN c.418_430del (p.Leu140AsnfsTer3; p.L140Nfs*3) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2 at supporting strength under the PTEN Expert Panel threshold for rarity.

3

This deletion causes a frameshift with premature termination after codon 140, and under the PTEN-specific PVS1 decision tree the premature stop is 5' to p.D375 (c.1121), supporting a loss-of-function effect.

4

SpliceAI predicts possible splice impact with a maximum delta score of 0.28, but this alone does not meet the PTEN Expert Panel requirement for concordant computational evidence for PP3 or BP4.

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 frameshift deletion predicted to cause p.(Leu140AsnfsTer3) [p.(L140Nfs*3)]. Under the PTEN-specific PVS1 decision tree, a nonsense or frameshift variant at or 5' to p.D375 (c.1121) in biologically relevant transcript NM_000314.8 meets PVS1 at very strong strength; c.418_430del is well 5' to this threshold and is consistent with a loss-of-function effect in PTEN.	cspec pvs1_gene_context pvs1_variant_assessment vcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n
PS1	N/A	PS1 applies to a different nucleotide change producing the same amino acid substitution or equivalent splice effect. This variant is a frameshift deletion, so PS1 is not applicable.	cspec
PS2	Not assessed	No confirmed de novo occurrence in an affected individual was identified, so PS2 is not assessed.	cspec
PS3	Not assessed	No well-established functional study specific to this deletion was identified. The PTEN Expert Panel phosphatase assay guidance in Mighell et al. applies to missense variants, and no RNA or other assay demonstrating a damaging effect for this variant was identified.	cspec vcep_m_m_c_2
PS4	Not assessed	No proband count, specificity score, or case-control enrichment data were identified for this variant, so PS4 is not assessed.	cspec clinvar
PM1	Not met	PM1 is specified for variants affecting PTEN catalytic motifs at residues 90-94, 123-130, or 166-168. This frameshift begins at Leu140, which is outside these defined motifs, so PM1 is not met.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. This observed allele frequency of 0 is below the PTEN Expert Panel PM2_Supporting threshold of <0.00001 (0.001%), with no subpopulation evidence exceeding the <0.00002 (0.002%) requirement, so PM2_Supporting is met.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is designated not applicable in the PTEN Expert Panel specification.	cspec
PM4	Not met	PM4 is specified for in-frame insertions or deletions affecting a catalytic motif or for stop-loss variants causing protein extension. This variant is a frameshift deletion with premature truncation, so PM4 is not met.	cspec
PM5	N/A	PM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense change has been established. This variant is a frameshift deletion, so PM5 is not applicable.	cspec
PM6	Not assessed	No assumed de novo occurrence in a patient with PTEN-related disease and no family history was identified, so PM6 is not assessed.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 is not assessed.	cspec
PP2	N/A	PP2 is specified for missense variants in PTEN. This variant is a frameshift deletion, so PP2 is not applicable.	cspec
PP3	Not assessed	SpliceAI predicts a possible splice effect with a maximum delta score of 0.28, but the PTEN Expert Panel requires concordant splicing prediction evidence for PP3 and this variant is already established as a truncating frameshift under PVS1. In the absence of additional concordant splice evidence, PP3 is not assessed.	cspec spliceai
PP4	N/A	PP4 is designated not applicable in the PTEN Expert Panel specification because phenotype specificity is incorporated into PS4 rules.	cspec
PP5	N/A	PP5 is designated not applicable in the PTEN Expert Panel specification.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency of 0 is below the PTEN Expert Panel BA1 threshold of >0.00056 (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 the observed allele frequency of 0 is below both the PTEN Expert Panel BS1 supporting range of 0.0000043 to 0.000043 and strong range of 0.000043 to 0.00056. BS1 is not met.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No observation of this variant in the homozygous state in a healthy or PTEN hamartoma tumor syndrome-unaffected individual was identified, so BS2 is not assessed.	cspec
BS3	Not assessed	No well-established functional study showing no damaging effect for this deletion was identified. The indexed Mighell phosphatase assay guidance applies to missense variants, and no RNA study showing no splicing impact for this variant was identified, so BS3 is not assessed.	cspec vcep_m_m_c_2
BS4	Not assessed	No lack-of-segregation data were identified for this variant, so BS4 is not assessed.	cspec
BP1	N/A	BP1 is designated not applicable in the PTEN Expert Panel specification.	cspec
BP2	Not assessed	No phase data showing this variant in trans with a pathogenic PTEN variant, or repeated cis/phase-unknown observations with different pathogenic PTEN variants, were identified. BP2 is not assessed.	cspec
BP3	N/A	BP3 is designated not applicable in the PTEN Expert Panel specification.	cspec
BP4	Not assessed	SpliceAI predicts a possible splice effect with a maximum delta score of 0.28, which is above the benign SpliceAI range of 0 to 0.2 specified by the PTEN Expert Panel, and no concordant benign splicing evidence was identified. BP4 is therefore not assessed.	cspec spliceai
BP5	Not assessed	No alternate highly penetrant molecular explanation with clearly non-overlapping PTEN-related clinical features was identified, so BP5 is not assessed.	cspec
BP6	N/A	BP6 is designated not applicable in the PTEN Expert Panel specification.	cspec
BP7	N/A	BP7 applies to synonymous or deep intronic variants with no predicted splicing impact. This variant is an exonic frameshift deletion, so BP7 is not applicable.	cspec

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.