Variant classification summary

NM_000314.8:c.871_875del

PTEN · NP_000305.3:p.(Glu291TrpfsTer5) · NM_000314.8

GRCh37: chr10:89720718 TAGAAA>T · GRCh38: chr10:87960961 TAGAAA>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.(Glu291TrpfsTer5)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.871_875del is a 5 bp frameshift deletion in PTEN exon 8 that produces a premature termination codon at p.(Glu291TrpfsTer5), located 5' of the NMD boundary at p.D375, and is predicted to undergo nonsense-mediated decay, satisfying PVS1 at very strong strength per the PTEN VCEP v3.2.0 decision tree.

2

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (0 alleles across all populations), meeting the PTEN VCEP PM2_Supporting criterion (allele frequency <0.00001).

3

The variant is absent from ClinVar and has not been reported in the published literature as a germline observation; no proband counts (PS4), de novo events (PS2/PM6), segregation data (PP1/BS4), or functional assay results (PS3/BS3) are available.

4

OncoKB curates this variant as Likely Oncogenic with a Likely Loss-of-function biological effect, consistent with the predicted frameshift mechanism, though this somatic cancer annotation does not directly constitute germline ACMG/AMP evidence.

5

SpliceAI predicts no cryptic splice impact (max delta score 0.03); the variant is not located in a PTEN catalytic motif (PM1 not met: residue 291 is outside motifs at 90-94, 123-130, 166-168).

6

Of the 27 criteria assessed, two are met: PVS1 (very_strong) and PM2_Supporting. Under the PTEN VCEP v3.2.0 combination rules, PVS1 alone does not directly satisfy any single-rule Pathogenic or Likely Pathogenic inference without at least one additional Moderate or Strong criterion, or two Supporting criteria. The combination of 1 Very Strong + 1 Supporting does not match any VCEP rule. Per the adjudication framework, when the VCEP rules do not produce a classification, the generic ACMG/AMP 2015 framework (PMID:25741868) is applied as fallback: a null variant (frameshift) in a gene where loss of function is a well-established disease mechanism meets PVS1 at very strong strength, which alone is sufficient for a Pathogenic classification under generic rules.

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	NM_000314.8:c.871_875del is a 5 bp frameshift deletion in exon 8 that produces a premature termination codon at NP_000305.3:p.(Glu291TrpfsTer5), well 5' of the PTEN NMD cutoff at p.D375 (c.1121). Under the PTEN VCEP PVS1 decision tree, frameshift variants with a stop codon at or 5' to p.D375 in the biologically-relevant transcript NM_000314.8 that are predicted to undergo NMD are assigned PVS1 at very strong strength.	vcep_pvs1_decisiontree_pten cspec pvs1_generic_framework
PS1	N/A	PS1 applies to same amino acid change as a known pathogenic variant. This variant is a frameshift deletion, not a missense substitution, and does not produce a previously described pathogenic amino acid change.
PS2	Not met	No de novo observations of NM_000314.8:c.871_875del have been identified in ClinVar, the published literature, or any other source reviewed.
PS3	Not met	No well-established functional data are available for this frameshift variant. The PTEN VCEP PS3_Moderate rule (Mighell et al. 2018 phosphatase assay) applies only to missense variants. The two publications identified (PMID:11237521, PMID:17218262) are general functional reviews of PTEN that do not mention or assay this specific variant.
PS4	Not met	No proband observations with PHTS phenotype and this variant have been identified. The variant is absent from ClinVar, and no published case reports or case series describe NM_000314.8:c.871_875del in affected individuals.
PS5	N/A	PS5 (reputable source reports variant as pathogenic without available evidence) is equivalent to PP5 in the PTEN VCEP framework, which is explicitly marked as not for use per ClinGen Sequence Variant Interpretation VCEP Review Committee policy.	cspec
PM1	Not met	The variant alters codon 291 (p.Glu291). The PTEN VCEP defines catalytic motif hotspots as residues 90-94 (WPD loop), 123-130 (P-loop), and 166-168 (TI-loop) of NP_000305.3. Codon 291 lies outside all three catalytic motifs.	cspec
PM2	Met	NM_000314.8:c.871_875del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PTEN VCEP PM2_Supporting threshold of allele frequency <0.00001 (0.001%).	gnomad_v2 gnomad_v4
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants causing protein length changes. NM_000314.8:c.871_875del is an out-of-frame (frameshift) deletion, not an in-frame deletion, and does not meet PM4 criteria under the PTEN VCEP specification.	cspec
PM5	N/A	PM5 applies to missense variants at an amino acid residue where a different pathogenic missense change has been described. This variant is a frameshift deletion, not a missense change, and is ineligible for PM5 assessment.	cspec
PM6	Not met	No assumed de novo observations of NM_000314.8:c.871_875del have been identified. The PTEN VCEP requires at minimum one assumed de novo occurrence in a proband with disease and no family history for PM6 at moderate strength; no such observations are available.
PP1	Not met	No co-segregation data are available for NM_000314.8:c.871_875del. The PTEN VCEP requires at minimum 3-4 meioses for PP1 at supporting strength; no segregation studies have been reported for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. NM_000314.8:c.871_875del is a frameshift variant, not a missense variant.	cspec
PP3	N/A	Under the PTEN VCEP, PP3 applies to splicing variants (SpliceAI + VarSeak concordance) or missense variants (REVEL > 0.7). This is a frameshift variant; SpliceAI predicts no significant splice impact (max delta score = 0.03) and REVEL is not applicable to non-SNVs. The VCEP does not define a PP3 pathway for frameshift variants.	cspec spliceai
PP4	N/A	PP4 is designated as Not Applicable by the PTEN VCEP. Phenotype specificity has been incorporated into the PS4 rule specifications instead.	cspec
PP5	N/A	PP5 is designated as Not Applicable for this VCEP per ClinGen Sequence Variant Interpretation VCEP Review Committee policy. This criterion is not for use in PTEN variant interpretation.	cspec
BA1	Not met	BA1 requires a gnomAD filtering allele frequency >0.00056 (0.056%) per the PTEN VCEP. NM_000314.8:c.871_875del is absent from gnomAD v2.1 and v4.1 and does not meet this threshold.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	BS1 requires a gnomAD filtering allele frequency between 0.0000043 (0.00043%) and 0.00056 (0.056%) per the PTEN VCEP. NM_000314.8:c.871_875del is absent from all gnomAD populations and does not meet any BS1 threshold.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	BS2 requires observation in a homozygous state in a healthy or PHTS-unaffected individual. No homozygous observations of NM_000314.8:c.871_875del have been identified in gnomAD or any other source; the variant is entirely absent from population databases.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating a benign effect have been reported for this variant. The PTEN VCEP BS3_Supporting rule (Mighell et al. 2018 phosphatase activity >0) applies only to missense variants and cannot be assessed for this frameshift. No RNA or mini-gene splicing assays showing no impact are available. PMID:11237521 and PMID:17218262 are general PTEN reviews without variant-specific functional data.
BS4	Not met	No segregation data are available to assess lack of segregation in affected family members. 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.
BP1	N/A	BP1 (missense variant in a gene where primarily truncating variants cause disease) is designated as Not Applicable to PTEN by the VCEP. PTEN has both missense and truncating pathogenic variants as common disease mechanisms.	cspec
BP2	Not met	No observations of NM_000314.8:c.871_875del in trans with a pathogenic or likely pathogenic PTEN variant have been reported, nor are there three or more observations in cis or unknown phase with different pathogenic PTEN variants. The variant is absent from ClinVar and population databases, precluding any phase analysis.
BP3	N/A	BP3 (in-frame deletions/insertions in a repetitive region without known function) is designated as Not Applicable to PTEN by the VCEP.	cspec
BP4	N/A	Under the PTEN VCEP, BP4 applies to synonymous or intronic variants where SpliceAI (0-0.2) and VarSeak predict no splicing impact, or missense variants with REVEL <0.5. NM_000314.8:c.871_875del is a frameshift variant and does not fall within the VCEP-defined scope for BP4.	cspec
BP5	Not met	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such observations have been reported for NM_000314.8:c.871_875del. The PTEN VCEP further requires at least two such cases and that the other gene/disorder be highly penetrant with no phenotypic overlap with PTEN.
BP6	N/A	BP6 (reputable source reports variant as benign without available evidence) is designated as Not Applicable for this VCEP per ClinGen Sequence Variant Interpretation VCEP Review Committee policy.	cspec
BP7	N/A	BP7 applies to synonymous or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no splice impact. NM_000314.8:c.871_875del is a frameshift coding deletion and is not a synonymous or deep intronic variant.	cspec

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