PTEN c.266C>A, p.Pro89His
NM_000314.8:c.266C>A
COSMIC ID: COSM6910917
Variant of Uncertain Significance (VUS)
This PTEN missense variant (p.P89H) is absent from population databases (PM2_Supporting) and has strong in silico support for deleteriousness (PP3_Supporting), but lacks functional, segregation, de novo, or case–control evidence, and PTEN assay data did not meet PS3 criteria. Therefore, it remains a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
PP3
Genetic Information
Gene & Transcript Details
Gene
PTEN
Transcript
NM_000314.8
MANE Select
Total Exons
9
Strand
Forward (+)
Reference Sequence
NC_000010.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000314.7 | RefSeq Select | 9 exons | Forward |
| NM_000314.5 | Alternative | 9 exons | Forward |
| NM_000314.4 | Alternative | 9 exons | Forward |
| NM_000314.3 | Alternative | 9 exons | Forward |
| NM_000314.6 | Alternative | 9 exons | Forward |
Variant Details
HGVS Notation
NM_000314.8:c.266C>A
Protein Change
P89H
Location
Exon 5
(Exon 5 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 89 in gene PTEN
Alternate Identifiers
COSM6910917
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.266C>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 89 in gene PTEN
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.951
0.951
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.98
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Use PTEN PVS1 decision tree" applicable to null variants (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletions) in a gene where LOF is a known mechanism. The evidence for this variant shows: it is a missense change (p.P89H), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: no known pathogenic variant produces the same p.P89H amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN pre-processing, the finding for PS3 is: "Score (-0.2664) did not meet threshold (-1.11) for PS3_Moderate". The evidence for this variant shows: phosphatase activity assay score of -0.2664, above the moderate strength threshold. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Probands with specificity score ≥16 (Very Strong), 4–15.5 (Strong), 2–3.5 (Moderate), 1–1.5 (Supporting)." The evidence for this variant shows: no proband specificity or case–control data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Located in a mutational hotspot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90–94, 123–130, 166–168." The evidence for this variant shows: position 89 is outside the defined catalytic motifs. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population." The evidence for this variant shows: not present in gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: PTEN-related PHTS is autosomal dominant and no trans observations are relevant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant shows: it is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before." The evidence for this variant shows: no other missense at residue 89 has been established as pathogenic. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Assumed de novo without confirmation of paternity/maternity." The evidence for this variant shows: no de novo assumptions are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows: PTEN has both missense and truncating pathogenic variants and benign missense variation is not demonstrably low. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Missense variants: REVEL score > 0.7." The evidence for this variant shows: REVEL=0.95, MetaSVM, MetaLR, PolyPhen-2, PrimateAI and Deogen2 predict damaging. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no phenotype or familial data specific to PTEN-related syndromes provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source classifies variant as pathogenic." The evidence for this variant shows: not present in ClinVar or other reputable databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Filtering allele frequency >0.00056 (0.056%)." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Observed in homozygous state in healthy or PHTS-unaffected individual." The evidence for this variant shows: no homozygous observations reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Well-established in vitro or in vivo functional studies show no damaging effect." The evidence for this variant shows: no functional studies demonstrating lack of impact. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Lack of segregation in affected members of two or more families." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants cause disease." The evidence for this variant shows: missense variants are a known mechanism in PTEN. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Observed in trans with a pathogenic PTEN variant or in cis with multiple pathogenic variants." The evidence for this variant shows: no cis/trans observations with other variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indels in a repetitive region without a known function." The evidence for this variant shows: it is a missense change, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact. Missense variants: REVEL score < 0.5." The evidence for this variant shows: REVEL=0.95 indicating damaging. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source classifies variant as benign or likely benign." The evidence for this variant shows: no such classification exists. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "A synonymous or intronic variant at or beyond +7/-21 with no predicted splicing impact." The evidence for this variant shows: it is a missense variant. Therefore, this criterion is not applied.