Variant classification summary

NM_000314.8:c.951_952del

PTEN · NP_000305.3:p.(Leu318TyrfsTer6) · NM_000314.8

GRCh37: chr10:89720799 TAC>T · GRCh38: chr10:87961042 TAC>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.(Leu318TyrfsTer6)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.951_952del is a frameshift deletion in exon 8 of PTEN resulting in a premature termination codon at p.(Leu318TyrfsTer6), located 5' of the p.D375 threshold and predicted to undergo nonsense-mediated decay, satisfying PVS1 at very strong strength per the PTEN VCEP decision tree.

2

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada across all populations, meeting PM2 at supporting strength per PTEN VCEP allele frequency threshold of < 0.001%.

3

No additional pathogenic or benign criteria are met. One very strong criterion (PVS1) and one supporting criterion (PM2) are applied. Per PTEN VCEP Rule 20, this combination of one very strong and one supporting criterion yields a classification of Likely Pathogenic.

Final determination: Rule20 in the ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 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	Frameshift variant NM_000314.8:c.951_952del introduces a premature termination codon at p.(Leu318TyrfsTer6), located at or 5' to p.D375 (c.1121) in biologically-relevant transcript NM_000314.8. The stop codon occurs ~55 nt upstream of the last exon-exon junction (exon 8/9 at c.1026/1027) and is predicted to undergo nonsense-mediated decay. Per PTEN VCEP PVS1 decision tree, this satisfies PVS1 at very strong strength.	cspec vcep_pvs1_decisiontree_pten pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No established pathogenic variant at the same amino acid position with the same change has been identified. This frameshift produces a novel premature termination, not matching a previously classified pathogenic variant.
PS2	Not met	No de novo observation with confirmed parentage has been identified for this variant in any available data source.
PS3	Not met	No variant-specific functional data available. The PTEN VCEP-designated functional assay (Mighell et al. 2018, PMID:29706350 via mmc2.xlsx) covers missense variants only and does not include this frameshift deletion. No other functional studies testing this exact variant were identified in the literature. OncoKB annotation of Likely Loss-of-function is a curated assertion, not direct experimental evidence for this variant.	oncokb
PS4	Not met	No proband count or case-control data available. The variant is absent from ClinVar with zero submissions, providing no patient-level observations to evaluate PS4 specificity scores or odds ratios.	clinvar
PS5	N/A	PS5 is not included in the PTEN VCEP specification (ClinGen PTEN Expert Panel v3.2).
PM1	Not met	The PTEN VCEP defines PM1 as limited to catalytic motif residues: 90-94 (WPD loop), 123-130 (P-loop), and 166-168 (TI-loop) per NP_000305.3. This variant is a frameshift at codon 318, located in the C2 domain well outside the VCEP-defined catalytic motifs. No statistically significant hotspot at this position was identified in cancerhotspots.org.	cspec
PM2	Met	Variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. Per PTEN VCEP specification, PM2 is applied at supporting strength for variants with allele frequency < 0.00001 (0.001%).	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM4	N/A	PM4 per PTEN VCEP applies to in-frame insertions or deletions impacting at least one catalytic motif residue, or variants causing protein extension. This variant is an out-of-frame (frameshift) deletion, not an in-frame deletion.
PM5	N/A	PM5 requires a missense change at an amino acid residue where a different missense change has been classified as pathogenic. This variant is a frameshift deletion (p.Leu318TyrfsTer6), not a missense substitution, and does not meet the requirement for same-residue missense comparison.	pm5_candidates
PM6	Not met	No de novo observation (assumed or confirmed) has been identified for this variant in the available data.
PP1	Not met	No co-segregation data available. No family studies reporting this variant with meiotic segregation counts were identified.
PP2	N/A	PP2 per PTEN VCEP applies specifically to missense variants in a gene with a low rate of benign missense variation. This variant is a frameshift deletion, not a missense substitution.
PP3	Not met	PP3 per PTEN VCEP applies to splicing variants (SpliceAI + VarSeak concordance) or missense variants (REVEL > 0.7). This is a frameshift deletion in the coding region. SpliceAI predicts no splice impact (max delta = 0.02), and REVEL/BayesDel scores are not available for non-SNV variants. No additional computational evidence supports a deleterious effect beyond what is already captured by PVS1.	spliceai
PP4	N/A	PP4 is designated Not Applicable by the PTEN VCEP. Phenotype specificity has been incorporated into the PS4 rule specifications.	cspec
PP5	N/A	PP5 is designated Not Applicable by the PTEN VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	BA1 per PTEN VCEP requires a gnomAD filtering allele frequency > 0.00056 (0.056%). The variant is absent from all gnomAD populations (AF = 0).	gnomad_v2 gnomad_v4 cspec
BS1	Not met	BS1 per PTEN VCEP requires a gnomAD filtering allele frequency >= 0.0000043 (0.00043%). The variant is absent from all gnomAD populations (AF = 0).	gnomad_v2 gnomad_v4 cspec
BS2	Not met	BS2 requires observation of the variant in the homozygous state in a healthy or PHTS-unaffected individual. No homozygous observations are reported in gnomAD or any other data source.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating a benign effect have been identified. The PTEN VCEP-designated functional assay (Mighell et al. 2018, mmc2.xlsx) is limited to missense variants and does not include this frameshift deletion.
BS4	Not met	No segregation data demonstrating lack of segregation in affected family members are available for this variant.
BP1	N/A	BP1 is designated Not Applicable for PTEN by the VCEP. This rule (missense variant in a gene where primarily truncating variants cause disease) is not applicable to PTEN.	cspec
BP2	Not met	No evidence that this variant has been observed in trans with a pathogenic or likely pathogenic PTEN variant, or in cis/unknown phase with at least three different pathogenic/likely pathogenic PTEN variants.
BP3	N/A	BP3 is designated Not Applicable for PTEN by the VCEP. This rule (in-frame deletions/insertions in a repetitive region) is not applicable to PTEN.	cspec
BP4	N/A	BP4 per PTEN VCEP applies to synonymous or intronic variants where SpliceAI and VarSeak predict no splicing impact. This is a coding frameshift deletion, not a synonymous or intronic variant.
BP5	Not met	No evidence that this variant has been found in cases with an alternate molecular basis for disease. PTEN VCEP requires at least two such cases with a highly penetrant alternate gene/disorder and no phenotypic overlap with PTEN.
BP6	N/A	BP6 is designated Not Applicable by the PTEN VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 per PTEN VCEP applies to synonymous (silent) or intronic variants at or beyond +7/-21 with no predicted splicing impact. This is a coding frameshift deletion, not a synonymous or intronic variant.

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.