Variant classification summary

NM_000314.8:c.1211G>T

PTEN · NP_000305.3:p.(Ter404LeuextTer8) · NM_000314.8

GRCh37: chr10:89725228 G>T · GRCh38: chr10:87965471 G>T

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Ter404LeuextTer8)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.1211G>T (p.Ter404LeuextTer8) is a stop-loss variant in PTEN that removes the native stop codon and extends the protein by 8 amino acids. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2_Supporting under the PTEN VCEP v3.2.

2

The variant is absent from ClinVar. It has been reported in COSMIC (COSV64296267) in two somatic cancer samples, but no germline disease associations have been established.

3

No functional data is available for this stop-loss variant. The PTEN VCEP PVS1 decision tree does not cover stop-loss variants (limited to nonsense, frameshift, splice site, and exon deletions). The Mighell et al. 2018 phosphatase saturation mutagenesis assay evaluates missense substitutions only and does not include stop-loss variants.

4

No de novo observations, segregation data, or case-control studies are available. No publications were identified that mention this specific variant.

5

With only PM2_Supporting met (absent from population databases) and all other criteria either not met or not applicable, this variant does not reach any classification threshold under the PTEN VCEP v3.2 combination rules and remains a Variant of Uncertain Significance (VUS). Notably, PM4 (protein extension from stop-loss) is flagged for human review — the VCEP PM4 rule explicitly covers stop-loss variants causing protein extension, and if applied at Moderate strength, the combination of PM4 + PM2_Supporting could support Likely Pathogenic under certain rule configurations.

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	N/A	NM_000314.8:c.1211G>T is a stop-loss variant (p.Ter404LeuextTer8) that removes the native stop codon and extends the protein by 8 amino acids. The PTEN VCEP PVS1 decision tree covers nonsense, frameshift, canonical splice site disruptions, and single/multi-exon deletions — stop-loss is not a null variant mechanism and is not included in the decision tree. Protein extension from stop-loss is addressed under PM4 in the VCEP framework.	cspec pvs1_generic_framework
PS1	Not met	No same amino acid change previously established as pathogenic has been identified at this position. The variant is absent from ClinVar, and no stop-loss variant at p.Ter404 with a different nucleotide change has been reported as pathogenic.	clinvar
PS2	Not met	No de novo observations have been reported for this variant. The literature search yielded no publications, and no de novo data is available in ClinVar or other curated sources.	clinvar
PS3	N/A	The PTEN VCEP PS3 criteria apply to splicing assay data (PS3_Strong) and missense variant phosphatase activity per Mighell et al. 2018 (PS3_Moderate, Cum_score ≤ -1.11). This is a stop-loss variant (p.Ter404LeuextTer8), not a missense change, and the Mighell saturation mutagenesis dataset (mmc2.xlsx, Table S2) only covers internal missense substitutions and nonsense variants. The variant is not present in the functional assay data. No splicing impact is predicted (SpliceAI max delta = 0.01).	cspec vcep_mmc2 spliceai
PS4	Not met	No proband counts or phenotype specificity scores are available. The variant is absent from ClinVar and no affected individuals have been reported in the literature. PS4 requires proband enumeration with specificity scoring per the PTEN VCEP, and no such data exists.	clinvar
PS5	N/A	PS5 is not a canonical ACMG/AMP criterion code. The standard ACMG/AMP 2015 framework and the PTEN VCEP v3.2 do not include a PS5 criterion.	cspec
PM1	Not met	The PTEN VCEP defines PM1 for residues in three catalytic motifs: WPD loop (residues 90-94), P-loop (residues 123-130), and TI-loop (residues 166-168) per NP_000305.3. Position 404 is the native stop codon at the extreme C-terminus, far downstream of all defined catalytic motifs. No mutational hotspot at this position has been identified (cancerhotspots.org: not significant).	cspec
PM2	Met	NM_000314.8:c.1211G>T 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%) in large sequenced populations.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	The PTEN VCEP PM5 rule applies to missense changes at an amino acid residue where a different missense change has been classified as pathogenic or likely pathogenic. NM_000314.8:c.1211G>T is a stop-loss variant (p.Ter404LeuextTer8), not a missense substitution. There is no reference amino acid at position 404 for missense comparison (the reference is a stop codon).	cspec pm5_candidates
PM6	Not met	No de novo observations (assumed or confirmed) have been reported for this variant. The literature search yielded no publications, and no de novo data is present in ClinVar.	clinvar
PP1	Not met	No co-segregation data is available. The variant is absent from ClinVar and no family studies have been published. The PTEN VCEP requires at least 3-4 meioses for PP1 at supporting strength.	clinvar
PP2	N/A	The PTEN VCEP PP2 criterion applies to missense variants in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. NM_000314.8:c.1211G>T is a stop-loss variant, not a missense substitution. PP2 is not applicable to non-missense variant types.	cspec
PP3	N/A	The PTEN VCEP PP3 criterion applies to splicing variants (SpliceAI + VarSeak concordance) or missense variants (REVEL >0.7). This is a stop-loss variant. SpliceAI predicts no splicing impact (max delta = 0.01). REVEL score is not available for this variant. BayesDel score (-0.375) is not included in the VCEP PP3 rules. No applicable computational evidence tier exists for stop-loss variants under the VCEP PP3 specification.	cspec spliceai bayesdel
PP4	N/A	The PTEN VCEP specifies that PP4 is Not Applicable; phenotype specificity has been incorporated into the PS4 rule specifications (Use 2).	cspec
PP5	N/A	PP5 is Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The PTEN VCEP explicitly prohibits use of PP5.	cspec
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0). The PTEN VCEP BA1 threshold requires a filtering allele frequency >0.00056 (0.056%), which is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD (allele frequency = 0). The PTEN VCEP BS1 threshold requires a filtering allele frequency ≥0.0000043 (0.00043%) for BS1_Supporting or ≥0.000043 (0.0043%) for BS1, neither of which is met.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No homozygous observations of this variant have been reported in healthy or PHTS-unaffected individuals. The variant is absent from gnomAD, and no homozygous data exists in ClinVar or the literature.	gnomad_v2 gnomad_v4 clinvar
BS3	N/A	The PTEN VCEP BS3_Strong applies to intronic or synonymous variants with splicing assays showing no impact. BS3_Supporting applies to the Mighell et al. 2018 phosphatase assay (Cum_score >0). This is a stop-loss variant — not a splicing variant (SpliceAI max delta 0.01) and not evaluated in the Mighell missense assay. The functional data available is not applicable to the BS3 framework for this variant type.	cspec vcep_mmc2 spliceai
BS4	Not met	No segregation data is available to assess lack of segregation in affected family members. The PTEN VCEP requires lack of segregation in one family for BS4_Supporting or two or more families for BS4.	clinvar
BP1	N/A	BP1 is explicitly Not Applicable to PTEN per the PTEN VCEP v3.2 specification.	cspec
BP2	Not met	No observations of this variant in trans with a pathogenic or likely pathogenic PTEN variant, nor in cis/unknown phase with different pathogenic PTEN variants, have been reported. The variant is absent from ClinVar and population databases.	clinvar
BP3	N/A	BP3 (in-frame deletions/insertions in repetitive regions) is not applicable to PTEN per the VCEP. Additionally, this is a single-nucleotide substitution (stop-loss), not an in-frame indel.	cspec
BP4	N/A	The PTEN VCEP BP4 criterion applies to synonymous or intronic variants (SpliceAI + VarSeak no impact) or missense variants (REVEL <0.5). This is a stop-loss variant. REVEL score is not available. The VCEP BP4 specification does not define computational evidence thresholds for stop-loss variants.	cspec spliceai
BP5	Not met	No cases have been identified where this variant was found in an individual with an alternate molecular basis for disease. The PTEN VCEP requires at least two such cases for BP5 application.	clinvar
BP6	N/A	BP6 is Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The PTEN VCEP explicitly prohibits use of BP6.	cspec
BP7	N/A	BP7 applies to synonymous (silent) or intronic variants at or beyond +7/-21 for which splicing algorithms predict no impact. NM_000314.8:c.1211G>T is a stop-loss variant that alters the protein sequence (p.Ter404LeuextTer8) — it is not synonymous and does not meet BP7 criteria.	cspec
PM3	N/A	PM3 is not applicable to PTEN per the VCEP. PTEN hamartoma tumor syndrome is an autosomal dominant disorder; PM3 applies to recessive disorders with trans phase detection.	cspec
PM4	N/A	PM4 is pre-triaged as trivially not_applicable. Note: NM_000314.8:c.1211G>T is a stop-loss variant causing protein extension (p.Ter404LeuextTer8), which is explicitly covered by the PTEN VCEP PM4 rule ('variants causing protein extension'). The user has directed that PM4 be skipped; if reassessed, PM4_Moderate would apply.	cspec

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