NM_000314.8:c.993C>A

PTEN · NP_000305.3:p.(Asp331Glu) · NM_000314.8

GRCh37: chr10:89720842 C>A · GRCh38: chr10:87961085 C>A

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PM2 supporting PP2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Asp331Glu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000314.8:c.993C>A (p.Asp331Glu) in PTEN has a cumulative fitness score of -0.106 in the Mighell et al. 2018 saturation mutagenesis assay, indicating near-wild-type phosphatase activity that does not meet PS3 or BS3 thresholds.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting VCEP PM2_Supporting (allele frequency <0.001%).

PP2_Supporting is applied as PTEN has a low rate of benign missense variation and missense variants are a well-established disease mechanism.

The variant does not reside in VCEP-defined catalytic motifs (residues 90-94, 123-130, 166-168) and is not in a statistically significant hotspot, so PM1 is not met.

REVEL score of 0.622 does not meet PP3 threshold (>0.7) or BP4 threshold (<0.5); computational evidence is indeterminate.

No pathogenic or likely pathogenic comparator variant at codon 331 was identified in ClinVar; PM5 is not met.

PVS1 is not applicable as this is a missense variant outside the scope of the PTEN PVS1 decision tree. PS2, PS4, PM6, PP1, BS4, BP2, and BP5 could not be assessed due to absence of clinical, de novo, segregation, or co-occurrence data.

With two supporting pathogenic criteria (PM2_Supporting, PP2_Supporting) and no moderate, strong, or very-strong criteria met, the variant does not reach Likely Pathogenic under the PTEN VCEP combination rules. The variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v3.2.0 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	This is a missense variant (c.993C>A, p.Asp331Glu). The PTEN VCEP PVS1 decision tree applies only to nonsense, frameshift, canonical GT-AG splice site, and CNV variants.	pvs1_gene_context pvs1_variant_assessment vcep_pvs1_decisiontree_pten
PS1	Not met	No prior pathogenic or likely pathogenic classification exists for the same amino acid change (p.Asp331Glu) at this residue. The variant is absent from ClinVar.	clinvar
PS2	Not assessed	No de novo observation data available for this variant.
PS3	Not met	D331E cumulative fitness score (Cum_score) of -0.106 from the Mighell et al. 2018 (PMID: 29706350) massively parallel phosphatase activity assay does not meet PS3_Moderate threshold (Cum_score ≤ -1.11) and does not indicate phosphatase activity <50% of wild-type for PS3_Supporting. SpliceAI predicts no splicing impact (max delta score = 0.00).	vcep_mmc2 spliceai
PS4	Not assessed	No proband or case-control data available. The variant is absent from ClinVar with no clinical submissions.	clinvar
PS5	Not assessed	PS5 is not defined by the ClinGen PTEN VCEP specification version 3.2.0. No VCEP rule framework exists for this criterion in the current gene-specific guideline.	cspec
PM1	Not met	Residue 331 (p.Asp331) resides in the C2 domain, not within the VCEP-defined catalytic motifs at residues 90-94, 123-130, or 166-168 of NP_000305.3. Does not lie in a statistically significant hotspot.	cspec
PM2	Met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the VCEP PM2_Supporting threshold of allele frequency <0.00001 (0.001%).	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM5	Not met	No pathogenic or likely pathogenic missense variant at codon 331 has been identified in ClinVar to serve as a comparator for the PM5 same-residue missense change rule.	clinvar pm5_candidates
PM6	Not assessed	No de novo observation data available for this variant.
PP1	Not assessed	No co-segregation data available for this variant.
PP2	Met	PTEN is a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease, meeting the VCEP PP2_Supporting criterion.	cspec
PP3	Not met	REVEL score of 0.622 does not meet the VCEP PP3 threshold of >0.7. BayesDel score of -0.042 does not support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00).	revel bayesdel spliceai cspec
PP4	N/A	The ClinGen PTEN VCEP specifies PP4 as Not Applicable; phenotype specificity has been incorporated into the PS4 rule specifications.	cspec
PP5	N/A	The ClinGen PTEN VCEP specifies PP5 as Not Applicable.	cspec
BA1	Not met	Variant is absent from gnomAD and does not exceed the VCEP BA1 allele frequency threshold of >0.00056 (0.056%).	gnomad_v2 gnomad_v4 cspec
BS1	Not met	Variant is absent from gnomAD and does not meet BS1 allele frequency thresholds (≥0.0000043 for BS1_Supporting; ≥0.000043 for BS1_Strong).	gnomad_v2 gnomad_v4 cspec
BS2	Not met	No homozygous observations in healthy or PHTS-unaffected individuals identified.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not met	BS3_Supporting requires phosphatase activity >0 per Mighell et al. 2018. D331E cumulative fitness score of -0.106 is not >0. BS3_Strong requires a splicing assay for intronic or synonymous variants, which is not applicable to this missense variant.	vcep_mmc2 cspec
BS4	Not assessed	No segregation data available to assess lack of segregation in affected family members.
BP1	N/A	The ClinGen PTEN VCEP specifies BP1 as Not Applicable.	cspec
BP2	Not assessed	No data available on co-occurrence in trans or cis with other pathogenic or likely pathogenic PTEN variants.
BP4	Not met	REVEL score of 0.622 is not <0.5, failing the VCEP BP4 threshold for missense variants. Multiple computational lines do not consistently suggest no impact.	revel bayesdel spliceai cspec
BP5	Not assessed	No data on an alternate molecular basis for disease in a case carrying this variant.
BP6	N/A	The ClinGen PTEN VCEP specifies BP6 as Not Applicable.	cspec
BP7	N/A	This is a missense variant, not a synonymous or intronic variant. BP7 applies only to synonymous or intronic variants at or beyond +7/-21 for which splicing algorithms predict no impact.	cspec

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.