PTEN c.182A>T, p.His61Leu
NM_000314.8:c.182A>T
COSM5227
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
0.956
Likely Pathogenic
COSMIC Recurrence
4 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
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.182A>T
Protein Change
H61L
Location
Exon 3
(Exon 3 of 9)
5'
Exon Structure (9 total)
3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 61: H61D, H61R
Alternate Identifiers
COSM5227
Variant interpretation based on transcript NM_000314.8
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications
0 publications
Clinical Statement
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
18
Reported mutations in this domain
0
50
100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (18 mutations).
PM1 criterion applied: Located in a mutational hot spot and/or critical and well-established functional domain.
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 61: H61D, H61R
PM5 criterion applied: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Functional Studies
Summary
The PTEN H61L variant results in reduced phosphatase activity as demonstrated in a yeast assay, indicating a loss of PTEN protein function.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.956
0.956
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Pathogenic
PP3 Applied
Yes
Additional Predictors
Pathogenic:
sift: D
polyphen_prediction: probably_damaging
mutationtaster: D
mutationassessor: H
fathmm: D
provean: D
metasvm: D
metalr: D
primateai: D
deogen2: D
Benign:
CADD: 5.39
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Very Strong - Use PTEN PVS1 decision tree." The evidence for this variant shows: it is a missense change (H61L) and 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 prior pathogenic H61L or equivalent variant at this amino acid. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Very Strong/Strong de novo occurrences with confirmation requirements." The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PS3
PS3 (Moderate)
Strength Modified
According to PTEN Pre-processing guidelines, the rule/finding for PS3 is: "Applied PS3_Moderate (Score -4.8086 < -1.11)." The evidence for this variant shows: phosphatase activity score of -4.8086, which is below the threshold of -1.11. Therefore, this criterion is applied at Moderate strength because the functional assay demonstrates a damaging effect per the PTEN-specific threshold.
PS4
PS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Probands with specificity score or increased prevalence in affected vs controls." The evidence for this variant shows: no case-control or proband specificity data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate - Located in a mutational hotspot or critical domain (residues 90-94, 123-130, 166-168)." The evidence for this variant shows: H61 is outside the defined PTEN hotspot residues. Therefore, this criterion is not applied.
PM2
PM2 (Supporting)
Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting - Absent in population Databases present at <0.00001 allele frequency in gnomAD." The evidence for this variant shows: not found in gnomAD. Therefore, this criterion is applied at Supporting strength because the variant is absent from large population databases.
PM3
PM3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Moderate - Observed in trans with a pathogenic PTEN variant for a recessive disorder." The evidence for this variant shows: no allelic phase or trans observation data. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate - Protein length changes due to in-frame indels or stop-loss variants." The evidence for this variant shows: it is a missense change with no protein length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate - Novel missense change at a residue where a different missense change is known pathogenic with BLOSUM62 score criteria." The evidence for this variant shows: no documented different pathogenic missense at residue 61. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Moderate - Assumed de novo without confirmation." The evidence for this variant shows: no de novo assumption data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting - 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, the rule for PP2 is: "Supporting - Missense variant in a gene with low rate of benign missense variation and where missense is a common disease mechanism." The evidence for this variant shows: insufficient data on benign missense rate and disease mechanism prevalence. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Supporting - Missense variants: REVEL score > 0.7." The evidence for this variant shows: a REVEL score of 0.96. Therefore, this criterion is applied at Supporting strength because computational predictions support a deleterious effect.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Supporting - 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 clinical data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting - Reputable source reports variant as pathogenic." The evidence for this variant shows: not found 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: "Stand Alone - gnomAD allele frequency > 0.00056." The evidence for this variant shows: allele frequency of 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong - gnomAD Filtering allele frequency from 0.000043 up to 0.00056." The evidence for this variant shows: allele frequency of 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong/Supporting - Observed homozygous in healthy or unaffected individual." The evidence for this variant shows: no homozygosity data in healthy individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong/Supporting - Functional studies show no damaging effect." The evidence for this variant shows: functional assay demonstrates damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong/Supporting - Lack of segregation in affected family members." 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, the rule for BP1 is: "Supporting - Missense variant in a gene where primarily truncating variants cause disease." The evidence for this variant shows: PTEN has both truncating and missense pathogenic variants. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Supporting - Observed in trans with a pathogenic PTEN variant or in cis multiple times." The evidence for this variant shows: no allelic phase or cis/trans data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting - In-frame indels in a repetitive region." The evidence for this variant shows: it is a missense change, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting - Multiple lines of computational evidence suggest no impact (REVEL < 0.5)." The evidence for this variant shows: REVEL of 0.96 indicates deleterious impact. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting - Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no such 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: "Supporting - Reputable source reports variant as benign." The evidence for this variant shows: no benign reports in reputable sources. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Supporting - Synonymous or intronic variant with no splicing impact." The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.