PTEN c.277C>A, p.His93Asn
NM_000314.8:c.277C>A
Likely Pathogenic
This PTEN missense variant meets two Moderate (PM1, PM5) and three Supporting (PM2, PP3, PP5) criteria under VCEP guidelines, consistent with a Likely Pathogenic classification.
ACMG/AMP Criteria Applied
PM1
PM2
PM5
PP3
PP5
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.277C>A
Protein Change
H93N
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 93 in gene PTEN
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.277C>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
Likely Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
48
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (48 mutations).
PM1 criterion applied.
Related Variants in This Domain
No evidence of other pathogenic variants at position 93 in gene PTEN
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.891
0.891
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: 5.78
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines: "PVS1 uses the PTEN PVS1 decision tree for predicted loss-of-function variants"; the rule for PVS1 is: "Very Strong Use PTEN PVS1 decision tree". The evidence for this variant shows: NM_000314.8:c.277C>A is a missense change (H93N), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant does not meet the loss-of-function requirement.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: "PS1: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change". The evidence for this variant shows: no other pathogenic variant yields H93N. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PS2: De novo observation in a patient with the disease and no family history". The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN pre-processing: "Result: Score (-0.5071) did not meet threshold (-1.11) for PS3_Moderate". The evidence for this variant shows: phosphatase activity score does not meet the VCEP-defined cutoff. Therefore, this criterion is not applied at Moderate strength.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: "PS4: Probands with specificity score ≥16 for Very Strong, 4–15.5 for Strong, 2–3.5 for Moderate, 1–1.5 for Supporting". The evidence for this variant shows: no case‐level specificity data. Therefore, this criterion is not applied.
PM1
PM1 (Moderate)
According to VCEP guidelines: "PM1: Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94". The evidence for this variant shows: H93 lies within the catalytic motif 90-94 of PTEN. Therefore, this criterion is applied at Moderate strength.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: "PM2: Absent in population databases at <0.00001 allele frequency". The evidence for this variant shows: c.277C>A is not present in gnomAD or other large controls. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: "PM3: For recessive disorders, detected in trans with a pathogenic variant". The evidence for this variant shows: no trans data and PTEN disease is autosomal dominant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines: "PM4: Protein length changes due to in-frame indels or stop-loss variants". The evidence for this variant shows: this is a missense change, not an indel or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines: "PM5: Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before". The evidence for this variant shows: other missense substitutions at codon 93 have been reported as pathogenic. Therefore, this criterion is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines: "PM6: Assumed de novo without confirmation". The evidence for this variant shows: no de novo information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: "PP1: Co‐segregation with disease in multiple affected family members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PP2: Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism". The evidence for this variant shows: insufficient data on benign missense rate in PTEN. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines: "PP3: REVEL score >0.7 for missense variants". The evidence for this variant shows: REVEL score is 0.89. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PP4: Phenotype specific for disease with single genetic etiology". The evidence for this variant shows: no phenotype data provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines: "PP5: Reputable source reports variant as pathogenic without available evidence". The evidence for this variant shows: ClinVar lists NM_000314.8:c.277C>A as Likely Pathogenic by one laboratory. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: "BA1: gnomAD allele frequency >0.00056". The evidence for this variant shows: absent in gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: "BS1: gnomAD allele frequency 0.000043–0.00056". The evidence for this variant shows: absent in gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: "BS2: Observed homozygous in healthy individual". The evidence for this variant shows: no homozygotes observed. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: "BS3: Well‐established functional studies show no damaging effect". The evidence for this variant shows: no such functional evidence. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: "BS4: Lack of segregation in affected members of two or more families". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP1: Missense in a gene where only truncating variants cause disease". The evidence for this variant shows: PTEN disease mechanism includes missense and truncating variants. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: "BP2: Observed in trans with a pathogenic variant". The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP3: In-frame indel in a repetitive region without a known function". The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: "BP4: REVEL score <0.5 for missense variants". The evidence for this variant shows: REVEL score is 0.89. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP5: Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no alternate molecular diagnosis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP6: Reputable source reports variant as benign without evidence". The evidence for this variant shows: no such report. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: "BP7: Synonymous or intronic variant predicted no splicing impact". The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.