Variant classification summary

NM_000314.8:c.927_937delinsT

PTEN · NP_000305.3:p.(Asp310ArgfsTer4) · NM_000314.8

GRCh37: chr10:89720776 AGATAATGACA>T · GRCh38: chr10:87961019 AGATAATGACA>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.(Asp310ArgfsTer4)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.927_937delinsT (p.Asp310ArgfsTer4) is a frameshift variant in exon 8 of PTEN, resulting in a premature termination codon at position 313. Per the PTEN-specific PVS1 decision tree, the stop codon lies 5' to the p.D375 (c.1121) NMD threshold, and the variant is predicted to undergo nonsense-mediated decay in the biologically-relevant transcript NM_000314.8. PVS1 is applied at very strong strength.

2

The variant is absent from all population databases, including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (0 alleles). Per the PTEN VCEP, PM2 is applied at supporting strength for variants absent from large sequenced populations.

3

This variant has not been reported in ClinVar and is absent from the somatic COSMIC database. No proband observations, co-segregation data, de novo reports, or functional studies were identified for this specific variant.

4

SpliceAI predicts no significant splicing impact (max delta score = 0.04), consistent with the variant's mechanism operating through protein truncation rather than aberrant splicing.

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.927_937delinsT is a frameshift variant predicted to result in a premature termination codon at p.Asp310ArgfsTer4 (p.313). Per the PTEN-specific PVS1 decision tree using transcript NM_000314.8, the stop codon occurs at position 313, which is 5' to the p.D375 (c.1121) NMD threshold, and the variant is predicted to undergo nonsense-mediated decay. The exon is present in the biologically-relevant transcript NM_000314.8. PVS1 is assigned at very strong strength.	vcep_pvs1_decisiontree_pten pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to variants causing the same amino acid change as a previously established pathogenic variant, or a different nucleotide substitution at the same position as a pathogenic splicing variant. This is a frameshift indel (NM_000314.8:c.927_937delinsT), not a single amino acid substitution or nucleotide substitution at a splice site. PS1 is not applicable to frameshift variants.
PS2	Not met	No de novo observation (confirmed or assumed) has been identified for NM_000314.8:c.927_937delinsT in the available evidence. PS2 requires a de novo occurrence in a patient with disease and no family history.
PS3	Not met	No variant-specific functional data is available for NM_000314.8:c.927_937delinsT. The PTEN VCEP specifies PS3 evidence from splicing assays, Mighell et al. 2018 phosphatase activity (missense-specific), or in vitro cellular assays. This frameshift variant is not a missense change and cannot be evaluated by the Mighell phosphatase assay. Neither of the two reviewed publications (PMID:11237521, PMID:17218262) reports experimental functional data for this variant.
PS4	Not met	No proband count or phenotype specificity score data is available for NM_000314.8:c.927_937delinsT. The PTEN VCEP requires proband counts with specificity scores to apply PS4 at any strength level. The variant is absent from ClinVar and no case-level observations were identified in the literature.
PS5	N/A	PS5 is not defined in the ClinGen PTEN Expert Panel specifications (Version 3.2). This criterion does not appear in the VCEP criteria set. The variant is a frameshift indel, and the generic PS5 criterion (novel missense change at a residue with another pathogenic missense) is also inapplicable to non-missense variants.
PM1	Not met	The PTEN VCEP defines PM1 for variants located in catalytic motifs: WPD loop (residues 90-94), P-loop (residues 123-130), and TI-loop (residues 166-168) of NP_000305.3. The variant p.Asp310ArgfsTer4 begins at position 310, which lies far C-terminal to all three defined catalytic motifs. The variant does not reside in a mutational hotspot as defined by cancerhotspots.org.
PM2	Met	NM_000314.8:c.927_937delinsT is absent from all population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Per the PTEN VCEP, PM2 is applied at supporting strength when a variant is absent or present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	The PTEN VCEP specifies PM4 for in-frame insertions or deletions impacting at least one residue in a catalytic motif, or for variants causing protein extension (stop-loss). NM_000314.8:c.927_937delinsT is a frameshift (out-of-frame) variant, not an in-frame deletion/insertion and not a stop-loss variant. PM4 is not applicable to frameshift variants under the PTEN VCEP.
PM5	N/A	The PTEN VCEP defines PM5 for a missense change at an amino acid residue where a different missense change has been determined to be pathogenic or likely pathogenic, with a BLOSUM62 score requirement. NM_000314.8:c.927_937delinsT is a frameshift indel, not a missense variant. The pm5_candidates analysis confirmed this variant is not eligible for classic same-residue missense PM5.	pm5_candidates
PM6	Not met	No assumed or confirmed de novo observation has been identified for NM_000314.8:c.927_937delinsT. The PTEN VCEP requires at minimum one assumed de novo occurrence in a proband with disease and no family history to apply PM6 at moderate strength.
PP1	Not met	No co-segregation data is available for NM_000314.8:c.927_937delinsT. The PTEN VCEP requires at minimum 3-4 meioses to apply PP1 at supporting strength. No family studies were identified in the literature.
PP2	N/A	The PTEN VCEP defines PP2 as a missense variant in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. NM_000314.8:c.927_937delinsT is a frameshift indel, not a missense variant. PP2 is not applicable to non-missense variants under the PTEN VCEP.
PP3	N/A	The PTEN VCEP defines PP3 for missense variants with REVEL score >0.7 or splicing variants with concordant SpliceAI and VarSeak predictions. NM_000314.8:c.927_937delinsT is a frameshift indel. REVEL and BayesDel scores are not available for indels. SpliceAI max delta score is 0.04, indicating no significant splice impact. The variant's pathogenicity is assessed through the PVS1 framework rather than in silico prediction algorithms designed for missense and splice variants.	spliceai
PP4	N/A	The ClinGen PTEN Expert Panel determined PP4 is not applicable for this VCEP. Phenotype specificity has been incorporated into the rule specifications for PS4.	cspec
PP5	N/A	PP5 is designated as Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee. This criterion is not for use under the PTEN VCEP framework.	cspec
BA1	Not met	The PTEN VCEP defines BA1 for variants with gnomAD filtering allele frequency >0.00056 (0.056%). NM_000314.8:c.927_937delinsT is absent from all gnomAD populations (v2.1, v4.1, Canada). BA1 is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The PTEN VCEP defines BS1 at strong strength for gnomAD filtering AF from 0.000043 to 0.00056, and at supporting strength for AF from 0.0000043 to 0.000043. NM_000314.8:c.927_937delinsT is absent from gnomAD (AF = 0). BS1 is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	The PTEN VCEP defines BS2 for a variant observed in the homozygous state in a healthy or PHTS-unaffected individual. NM_000314.8:c.927_937delinsT is absent from all population databases with no homozygous observations. No clinical reports of homozygous or healthy adult carriers were identified.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate a lack of damaging effect for NM_000314.8:c.927_937delinsT. The PTEN VCEP BS3_Supporting rule references the Mighell et al. 2018 phosphatase assay (missense-specific), which does not apply to this frameshift variant. No splicing assay demonstrating no impact is available (SpliceAI max delta = 0.04 confirms no predicted splice effect, but BS3 requires experimental functional data, not in silico prediction alone).
BS4	Not met	The PTEN VCEP requires lack of segregation in affected members of two or more families for BS4 at strong strength, or one family for supporting strength. No segregation data is available for NM_000314.8:c.927_937delinsT.
BP1	N/A	The ClinGen PTEN Expert Panel has determined that BP1 is not applicable to PTEN. Per the VCEP: 'This rule is not applicable to PTEN.'	cspec
BP2	Not met	The PTEN VCEP defines BP2 for a variant observed in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis/phase unknown with different P/LP PTEN variants. No such observations are available for NM_000314.8:c.927_937delinsT.
BP3	N/A	The ClinGen PTEN Expert Panel has determined that BP3 is not applicable to PTEN. Per the VCEP: 'This rule is not applicable to PTEN.'	cspec
BP4	Not met	The PTEN VCEP defines BP4 for synonymous or intronic variants where SpliceAI (0-0.2) and VarSeak predict no splicing impact, or for missense variants with REVEL <0.5. NM_000314.8:c.927_937delinsT is a frameshift variant whose pathogenic mechanism operates through protein truncation and nonsense-mediated decay, not through altered splicing. While SpliceAI predicts no splice impact (max delta = 0.04), BP4 is designed for variants where splicing is the primary concern. The frameshift's established deleterious mechanism through PVS1 does not support application of BP4.	spliceai
BP5	Not met	The PTEN VCEP defines BP5 for a variant found in a case with an alternate molecular basis for disease, requiring at least two such cases with the alternate gene being highly penetrant and no phenotypic overlap with PTEN. No such cases have been identified for NM_000314.8:c.927_937delinsT.
BP6	N/A	BP6 is designated as Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee. This criterion is not for use under the PTEN VCEP framework.	cspec
BP7	N/A	The PTEN VCEP defines BP7 for synonymous or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor creation of a new splice site. NM_000314.8:c.927_937delinsT is a frameshift coding indel, not a synonymous or intronic variant. BP7 is not applicable.

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