Variant classification summary

NM_000314.8:c.923del

PTEN · NP_000305.3:p.(Arg308LeufsTer9) · NM_000314.8

GRCh37: chr10:89720771 CG>C · GRCh38: chr10:87961014 CG>C

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.(Arg308LeufsTer9)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.923del is a frameshift deletion in PTEN exon 8 resulting in a premature termination codon at p.Arg308LeufsTer9, which lies 5' to the p.D375 threshold and is predicted to undergo NMD, meeting PVS1 under the PTEN VCEP decision tree.

2

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength under PTEN VCEP (allele frequency < 0.001%).

3

Under the PTEN VCEP combination rules (Version 3.2), PVS1 alone with PM2_Supporting does not satisfy any pathogenic or likely pathogenic classification rule. The variant has not been reported in ClinVar, has no de novo observations, no co-segregation data, and no variant-specific functional data.

4

This variant has been observed in 7 somatic cancer samples (COSMIC: COSV64291945), and OncoKB classifies it as Likely Oncogenic with a predicted loss-of-function effect, consistent with PTEN's tumor suppressor role. However, somatic observations do not directly contribute to germline ACMG/AMP classification under the PTEN VCEP.

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	NM_000314.8:c.923del is a frameshift deletion in exon 8 producing a premature termination codon at p.(Arg308LeufsTer9). The new stop codon at position 316 lies 5' to the p.D375 (c.1121) positional threshold and is predicted to undergo nonsense-mediated decay (NMD). Exon 8 is present in the biologically-relevant transcript NM_000314.8. Under the PTEN VCEP PVS1 decision tree, a frameshift variant with stop codon 5' to p.D375 predicted to undergo NMD in a biologically-relevant transcript is assigned PVS1.	vcep_pvs1_decisiontree_pten pvs1_generic_framework
PS1	N/A	PS1 applies to the same amino acid change as a previously established pathogenic variant or a different variant at the same nucleotide position as a known pathogenic splicing variant. This is a frameshift deletion, not a missense or splicing variant.
PS2	Not met	No de novo observation reported in ClinVar, the literature, or any database. Under PTEN VCEP, PS2 requires a confirmed de novo observation in a patient with disease and no family history.
PS3	Not met	PTEN VCEP specifies PS3_Moderate for phosphatase activity ≤ -1.11 per Mighell et al. 2018 (PMID: 29706350), which applies only to missense variants. The mmc2.xlsx saturation mutagenesis dataset covers missense variants exclusively. This is a frameshift deletion; no variant-specific functional data from RNA assay, mini-gene, or other splicing/functional assay is available. The two publications in the literature packet (PMID: 11237521, PMID: 17218262) are gene-level functional reviews that do not mention NM_000314.8:c.923del.
PS4	Not met	No probands with specificity scores available for this variant. The variant is absent from ClinVar and no case-control studies or clinical cohorts reporting this variant were identified. Under PTEN VCEP, PS4 requires probands with specificity scores ≥ 1 for any strength level.
PS5	N/A	PS5 is not a criterion defined in the PTEN VCEP framework (ClinGen PTEN Expert Panel Specifications Version 3.2) or in the standard ACMG/AMP 2015 criteria.
PM1	Not met	PTEN VCEP defines PM1 for residues in catalytic motifs: 90-94, 123-130, and 166-168 (NP_000305.3). The variant affects codon 308 (p.Arg308LeufsTer9), which lies outside these defined catalytic motifs. Although the frameshift truncates the C-terminal C2 domain and PDZ-binding motif, the VCEP specification limits PM1 to the three catalytic motif regions.	cspec
PM2	Met	NM_000314.8:c.923del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under PTEN VCEP, PM2_Supporting is applied when allele frequency is < 0.00001 (0.001%) in gnomAD or another large sequenced population.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 under PTEN VCEP applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif, or variants causing protein extension. This is a frameshift (out-of-frame) deletion evaluated under PVS1, not an in-frame deletion or stop-loss variant.
PM5	N/A	PM5 under PTEN VCEP applies to missense changes at an amino acid residue where a different missense change has been determined to be pathogenic or likely pathogenic. This is a frameshift deletion, not a missense change.
PM6	Not met	No assumed or confirmed de novo observations identified in ClinVar, the literature, or any database. Under PTEN VCEP, PM6 requires at least one assumed de novo observation in a proband with disease and no family history.
PP1	Not met	No co-segregation data available for this variant. Under PTEN VCEP, PP1 requires at least 3-4 meioses for supporting-level evidence.
PP2	N/A	PP2 under PTEN VCEP applies specifically to missense variants in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. This is a frameshift deletion.
PP3	N/A	PP3 under PTEN VCEP applies to missense variants with REVEL score > 0.7, or to splicing variants with concordance of SpliceAI and VarSeak. This is a frameshift deletion; REVEL is not applicable (not a single nucleotide variant), and SpliceAI shows no significant splice impact (max delta 0.02).
PP4	N/A	PP4 is marked Not Applicable by the PTEN VCEP. Phenotype specificity has been incorporated into the rule specifications for PS4 Use 2.	cspec
PP5	N/A	PP5 is marked Not Applicable by the PTEN VCEP. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	PTEN VCEP applies BA1 when gnomAD filtering allele frequency exceeds 0.00056 (0.056%). This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.	gnomad_v2 gnomad_v4
BS1	Not met	PTEN VCEP applies BS1_Strong at AF 0.000043-0.00056 and BS1_Supporting at AF 0.0000043-0.000043. This variant is absent from gnomAD (AF = 0).	gnomad_v2 gnomad_v4
BS2	Not met	PTEN VCEP applies BS2 when the variant is observed in the homozygous state in a healthy or PHTS-unaffected individual. No homozygous observations have been reported for this variant in any population database.	gnomad_v2 gnomad_v4
BS3	Not met	PTEN VCEP specifies BS3 for functional studies showing no damaging effect. BS3_Supporting applies for phosphatase activity > 0 per Mighell et al. 2018 (missense variants only). This is a frameshift deletion; no functional data demonstrating no damaging effect is available.
BS4	Not met	PTEN VCEP applies BS4 when there is a lack of segregation in affected family members. No segregation data is available for this variant.
BP1	N/A	BP1 is marked Not Applicable by the PTEN VCEP. This criterion applies to missense variants in genes where a truncating mechanism is primarily causative.	cspec
BP2	Not met	PTEN VCEP applies BP2 when the variant is observed in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis/unknown phase with different P/LP PTEN variants. No such observations have been reported.
BP3	N/A	BP3 is marked Not Applicable by the PTEN VCEP. This criterion applies to in-frame deletions/insertions in repetitive regions.	cspec
BP4	N/A	BP4 under PTEN VCEP applies to synonymous or intronic variants where SpliceAI and VarSeak predict no splicing impact. This is a frameshift deletion, not a synonymous or intronic variant.
BP5	Not met	PTEN VCEP applies BP5 when the variant is found in a case with an alternate molecular basis for disease, requiring at least two such cases. No cases with an alternate molecular basis have been identified for this variant.
BP6	N/A	BP6 is marked Not Applicable by the PTEN VCEP. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 under PTEN VCEP applies to synonymous (silent) or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no impact. This is a frameshift coding 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.