Variant classification summary

NM_000314.8:c.844G>T

PTEN · NP_000305.3:p.(Gly282Ter) · NM_000314.8

GRCh37: chr10:89720693 G>T · GRCh38: chr10:87960936 G>T

Gene: PTEN Transcript: NM_000314.8

Final call

Pathogenic

PVS1 very strong PS3 moderate PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Gly282Ter)

gnomAD AF

0.0 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): c.844G>T is a nonsense variant producing a premature termination codon at position 282 (p.Gly282Ter), located well 5' to the p.D375 threshold in exon 8 of the biologically-relevant transcript NM_000314.8. Per the PTEN VCEP decision tree, this is predicted to undergo NMD and is assigned PVS1 at Very Strong strength.

2

PS3 (Moderate): The Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis functional assay demonstrates a cumulative fitness score of -3.248 for p.Gly282Ter, indicating severely depleted phosphatase activity and meeting the PTEN VCEP PS3_Moderate threshold of <= -1.11.

3

PM2 (Supporting): The variant is absent from gnomAD v2.1 and has an allele frequency of 0 in gnomAD v4.1 (0/1,609,868 alleles), satisfying the PTEN VCEP PM2_Supporting criterion of <0.00001 (0.001%).

4

PM1 not met: Codon 282 lies outside the PTEN catalytic motifs (residues 90-94, 123-130, 166-168) and is not in a statistically significant mutational hotspot.

5

Combined classification: 1 Very Strong (PVS1) + 1 Moderate (PS3) + 1 Supporting (PM2) meets PTEN VCEP Rule 10 (Likely Pathogenic). Insufficient evidence for Pathogenic: no Strong-level criteria met, and only 1 Supporting criterion (Rule 4 requires >=2 Supporting for Pathogenic with PVS1).

Final determination: Rule3 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 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	Nonsense variant at codon 282 (c.844G>T, p.Gly282Ter) in exon 8 of PTEN (NM_000314.8). The stop codon occurs well 5' to the p.D375 (c.1121) positional threshold and is predicted to undergo nonsense-mediated decay. Per the PTEN VCEP PVS1 decision tree, a nonsense variant with stop codon at or 5' to p.D375 in the biologically-relevant transcript NM_000314.8 is assigned PVS1 at Very Strong strength.	vcep_pvs1_decisiontree_pten pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No previously established pathogenic variant resulting in the same amino acid change (p.Gly282Ter) was identified in ClinVar or the literature. The ClinVar entry for this variant (VCV004856217) is classified as Uncertain Significance by a single submitter. No other nucleotide change producing p.Gly282Ter has been classified as pathogenic or likely pathogenic.	clinvar
PS2	Not assessed	No de novo observation data are available. No publication or database entry reports this variant as occurring de novo in a patient with PTEN-hamartoma tumor syndrome and no family history.
PS3	Met	The Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis functional assay reports a cumulative fitness score of -3.248 for p.Gly282Ter, which is well below the PTEN VCEP PS3_Moderate threshold of <= -1.11. This indicates severely depleted phosphatase activity, confirming a damaging effect on the gene product.	vcep_mmc2
PS4	Not assessed	No proband or case-control data are available to calculate a specificity score or compare variant prevalence in affected individuals versus controls.
PS5	N/A	PS5 is not a recognized ACMG/AMP criterion code. The standard ACMG/AMP pathogenic criteria are PVS1, PS1-PS4, PM1-PM6, PP1-PP5. No PS5 criterion exists in the framework.
PM1	Not met	Codon 282 is not located within any of the PTEN VCEP-specified catalytic motifs (residues 90-94, 123-130, 166-168 per NP_000305.3). The variant also does not lie in a statistically significant mutational hotspot.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and has an allele frequency of 0 in gnomAD v4.1 (0/1,609,868 alleles), meeting the PTEN VCEP PM2_Supporting threshold of <0.00001 (0.001%). No subpopulation exceeds the 0.00002 (0.002%) threshold.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a missense change at an amino acid residue where a different missense change has been determined to be pathogenic or likely pathogenic. c.844G>T is a nonsense variant producing a premature termination codon (p.Gly282Ter), not a missense change.
PM6	Not assessed	No de novo observations are reported for this variant. No proband data with confirmed or assumed de novo status and no family history of PTEN-hamartoma tumor syndrome are available.
PP1	Not assessed	No co-segregation data are available. No family studies reporting segregation of c.844G>T with disease in multiple affected family members were identified.
PP2	N/A	PP2 is specified for missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. c.844G>T is a nonsense variant, not a missense change.
PP3	N/A	Per PTEN VCEP, PP3 applies to missense variants (REVEL > 0.7) or splicing variants (concordance of SpliceAI and VarSeak). c.844G>T is a nonsense variant. The deleterious impact of protein truncation is captured by PVS1; applying PP3 would constitute double-counting of the same evidence.
PP4	N/A	The PTEN VCEP specifies PP4 as Not Applicable; phenotype specificity has been incorporated into the PS4 rule specifications.
PP5	N/A	The PTEN VCEP specifies PP5 as Not Applicable.
BA1	Not met	The PTEN VCEP BA1 threshold requires a gnomAD filtering allele frequency > 0.00056 (0.056%). This variant has AF = 0 in gnomAD v4.1 (0/1,609,868 alleles) and is absent from gnomAD v2.1, far below the BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The PTEN VCEP BS1_Strong threshold requires a gnomAD filtering allele frequency from 0.000043 (0.0043%) to 0.00056 (0.056%). This variant has AF = 0 in gnomAD v4.1, below the BS1 range.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observations are reported in gnomAD. The variant has 0 homozygotes in gnomAD v4.1. No observation in the homozygous state in a healthy or PHTS-unaffected individual has been identified.	gnomad_v4
BS3	Not met	The Mighell et al. 2018 functional assay reports a cumulative fitness score of -3.248 for p.Gly282Ter, indicating severely depleted phosphatase activity. The PTEN VCEP BS3_Supporting threshold requires phosphatase activity >0 per Mighell et al. 2018, which is not met. No functional evidence supports a benign effect.	vcep_mmc2
BS4	Not assessed	No segregation data are available to evaluate lack of segregation in affected family members.
BP1	N/A	The PTEN VCEP specifies BP1 as Not Applicable.
BP2	Not assessed	No evidence is available regarding observation of this variant in trans with a pathogenic or likely pathogenic PTEN variant, or in cis/phase unknown with multiple pathogenic/likely pathogenic PTEN variants.
BP4	Not met	The PTEN VCEP BP4 specifies REVEL score < 0.5 for missense variants, but REVEL is not available for this nonsense variant. SpliceAI delta score is 0.04, indicating no significant splice impact, but this alone is insufficient for BP4 in a nonsense variant. BayesDel score of 0.653 suggests a deleterious effect rather than no impact.	spliceai bayesdel
BP5	Not assessed	No evidence is available regarding an alternate molecular basis for disease in a patient carrying this variant. No case with a confirmed highly penetrant pathogenic variant in another gene has been reported.
BP6	N/A	The PTEN VCEP specifies BP6 as Not Applicable.
BP7	N/A	BP7 applies to synonymous (silent) or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no splice impact. c.844G>T is a nonsense variant resulting in a premature termination codon.

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