Variant classification summary

NM_000314.8:c.389_405delinsTAACTGGTGTAATGATG

PTEN · NP_000305.3:p.(Arg130_Ile135delinsLeuThrGlyValMetMet) · NM_000314.8

GRCh37: chr10:89692905 GAACTGGTGTAATGATA>TAACTGGTGTAATGATG · GRCh38: chr10:87933148 GAACTGGTGTAATGATA>TAACTGGTGTAATGATG

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PM1 moderate PM2 supporting PM4 moderate

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Arg130_Ile135delinsLeuThrGlyValMetMet)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.389_405delinsTAACTGGTGTAATGATG is an in-frame deletion-insertion in exon 5 of PTEN, resulting in substitution of six residues (p.Arg130_Ile135delinsLeuThrGlyValMetMet). Residue Arg130 is the terminal residue of the P-loop/phosphatase core catalytic motif (NP_000305.3 residues 123-130), a critical functional domain defined by the ClinGen PTEN Expert Panel.

2

The variant is absent from gnomAD v2.1 and v4.1 population databases, satisfying PM2 at supporting strength per PTEN VCEP specifications.

3

The variant alters the P-loop catalytic motif, satisfying PM1 at moderate strength per PTEN VCEP (catalytic motifs defined as residues 90-94, 123-130, 166-168). As an in-frame deletion-insertion impacting a catalytic motif residue, PM4 also applies at moderate strength per PTEN VCEP specification.

4

No variant-specific functional, segregation, de novo, or case-level evidence is available. Four publications provided in the literature packet (PMID:10866302, PMID:32350270, PMID:32366478, PMID:9467011) do not mention this variant. The Mighell et al. 2018 saturation mutagenesis assay (mmc2.xlsx) covers missense variants only and does not include in-frame indels.

5

Per PTEN VCEP combination rules, two moderate criteria (PM1, PM4) and one supporting criterion (PM2_Supporting) are insufficient to reach Likely Pathogenic classification. The variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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	Not met	PTEN VCEP PVS1 decision tree applies to nonsense, frameshift, and canonical splice site variants. NM_000314.8:c.389_405delinsTAACTGGTGTAATGATG is an in-frame deletion-insertion that does not introduce a premature stop codon or disrupt the reading frame; it does not fall within any PVS1 decision tree branch.	vcep_pvs1_decisiontree_pten cspec
PS1	Not met	No previously established pathogenic variant with the same amino acid change (p.Arg130_Ile135delinsLeuThrGlyValMetMet) has been identified. This is a novel 6-residue in-frame substitution not matching any known pathogenic variant.	clinvar cspec
PS2	Not met	No de novo observation has been reported for this variant. No proband or family history data is available in the case materials.
PS3	Not met	No variant-specific functional data is available. The PTEN VCEP PS3_Moderate pathway via Mighell et al. 2018 (PMID:29706350) phosphatase activity assay applies to missense variants only and does not cover in-frame indels. The four papers provided in the literature packet (PMID:10866302, PMID:32350270, PMID:32366478, PMID:9467011) do not mention this variant.	cspec vcep_mmc2
PS4	Not met	No proband or case-level data is available to calculate a specificity score or assess prevalence in affected individuals. PTEN VCEP PS4 requires proband counts with phenotype specificity scoring.	cspec
PS5	N/A	PS5 is not a recognized ACMG/AMP criterion. Not included in the PTEN VCEP specifications.
PM1	Met	This variant alters residues 130-135 of NP_000305.3. Residue 130 (Arg130) is the terminal residue of the P-loop/phosphatase core catalytic motif defined by the PTEN VCEP as residues 123-130. The variant replaces Arg130 with Leu, directly disrupting a critical catalytic domain.	cspec
PM2	Met	The variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), meeting the PTEN VCEP PM2_Supporting threshold of allele frequency <0.00001 (0.001%).	gnomad_v2 gnomad_v4 cspec
PM4	Met	NM_000314.8:c.389_405delinsTAACTGGTGTAATGATG is an in-frame deletion-insertion that alters residues 130-135, including residue Arg130 which lies within the P-loop catalytic motif (residues 123-130). Per PTEN VCEP specification, PM4 applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif specified under PM1.	cspec
PM5	N/A	PM5 is a missense-specific criterion requiring a different missense change at the same residue as a known pathogenic missense variant. This variant is a 6-residue in-frame deletion-insertion, not a single-residue missense substitution. PM5 candidate analysis confirmed not applicable.	pm5_candidates cspec
PM6	Not met	No de novo observation (assumed or confirmed) has been reported for this variant in any proband with PHTS or related phenotype.
PP1	Not met	No co-segregation data is available. PTEN VCEP requires at least 3-4 meioses for PP1 at supporting strength.
PP2	N/A	PTEN VCEP PP2 applies specifically to missense variants in a gene with a low rate of benign missense variation. This variant is an in-frame deletion-insertion, not a single-residue missense change.	cspec
PP3	Not met	PTEN VCEP PP3 applies to missense variants with REVEL score >0.7 or splicing variants with concordant in silico predictions. REVEL does not compute scores for in-frame indels. SpliceAI predicts no significant splice impact (max delta score 0.03). No computational evidence supports a deleterious effect for this variant type.	spliceai cspec
PP4	N/A	PTEN VCEP specifies PP4 as Not Applicable; phenotype specificity has been incorporated into PS4 Use 2 within this framework.	cspec
PP5	N/A	PTEN VCEP specifies PP5 as Not Applicable per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Not met	The variant is absent from gnomAD. PTEN VCEP BA1 threshold of filtering allele frequency >0.00056 (0.056%) is not met.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	The variant is absent from gnomAD. PTEN VCEP BS1 threshold of filtering allele frequency ≥0.000043 (0.0043%) is not met.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	No observation of this variant in the homozygous state in a healthy or PHTS-unaffected individual has been reported.	gnomad_v2 gnomad_v4 cspec
BS3	Not met	No functional studies demonstrating no damaging effect on protein function are available for this variant. The PTEN VCEP BS3_Supporting pathway via Mighell et al. 2018 applies to missense variants with phosphatase activity >0 and does not cover in-frame indels.	cspec vcep_mmc2
BS4	Not met	No segregation data is available to demonstrate lack of segregation in affected family members.
BP1	N/A	PTEN VCEP specifies BP1 as Not Applicable; this rule is not applicable to PTEN as both truncating and missense variants are known mechanisms of disease.	cspec
BP2	Not met	No observation of this variant in trans with a pathogenic or likely pathogenic PTEN variant, nor three or more observations in cis/unknown phase with different pathogenic/likely pathogenic PTEN variants.
BP3	N/A	PTEN VCEP specifies BP3 as Not Applicable; this rule is not applicable to PTEN.	cspec
BP4	N/A	PTEN VCEP BP4 applies to synonymous or intronic variants where in silico models predict no splicing impact, and to missense variants with REVEL score <0.5. This variant is an in-frame coding deletion-insertion; BP4 is not applicable to this variant type.	cspec
BP5	Not met	No evidence that this variant has been found in a case with an alternate molecular basis for disease. PTEN VCEP requires at least two such cases.
BP6	N/A	PTEN VCEP specifies BP6 as Not Applicable per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	N/A	BP7 applies to synonymous or intronic variants with no predicted splice impact. This variant is a coding in-frame deletion-insertion, not a synonymous or intronic variant.	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.