PTEN c.136T>C, p.Tyr46His
NM_000314.8:c.136T>C
COSMIC ID: COSM3397282
Pathogenic
The variant shows moderate-strength functional impact (PS3_Moderate), absence from population (PM2), deleterious computational predictions (PP3), and a pathogenic missense at the same residue (PM5). These criteria together support a Likely Pathogenic classification.
ACMG/AMP Criteria Applied
PS3
PM2
PM5
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.136T>C
Protein Change
Y46H
Location
Exon 2
(Exon 2 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 46: Y46D
Alternate Identifiers
COSM3397282
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.136T>C
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
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 46: Y46D
PM5 criterion applied.
Functional Summary
The PTEN Y46H variant results in reduced phosphatase activity in a yeast assay, indicating a loss of PTEN protein function.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.965
0.965
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: 5.30
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, PVS1 applies to null variants following the PTEN PVS1 decision tree; this variant is a missense change. The evidence for this variant shows it is not predicted to result in loss of the reading frame. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 (Strong) requires the same amino acid change as a previously established pathogenic variant. The evidence for this variant shows a novel Y46H change with no identical pathogenic amino acid change reported. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 (Strong) requires confirmed de novo occurrence in a patient. No de novo information is available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing, the rule for PS3_Moderate is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Phosphatase activity ≤ -1.11 per Mighell et al. 2018". The evidence for this variant shows a phosphatase activity score of -2.7199, which is below -1.11. Therefore, this criterion is applied at Moderate strength.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires an increased prevalence in affected individuals or probands with specificity score ≥4. No case or specificity score data are available for this variant. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 (Moderate) applies if the variant is located in a PTEN catalytic motif (residues 90–94, 123–130, 166–168). The evidence for this variant shows position 46, outside defined hotspots. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 (Supporting) is: "Absent in population databases present at <0.00001 allele frequency in gnomAD." The evidence for this variant shows 0% frequency in gnomAD. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to variants detected in trans with a pathogenic variant in a recessive disorder. PTEN-associated disease is autosomal dominant, and no trans observations are reported. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, PM4 (Moderate) applies to in-frame indels or stop-loss variants. This variant is a missense change. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines, PM5 (Moderate) is: "Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before, with equal or more deleterious BLOSUM62 score." The evidence for this variant shows a previously reported pathogenic missense at residue 46 (e.g., Y46C in ClinVar) and the BLOSUM62 score for the histidine substitution is equal or more deleterious. Therefore, this criterion is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 (Strong) applies to assumed de novo occurrences without confirmation. No de novo assumptions are reported. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires co-segregation in multiple affected family members. No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 (Supporting) requires a missense variant in a gene with a low rate of benign missense variation. Insufficient data on benign missense rate in PTEN are available here. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, PP3 (Supporting) is: "Multiple lines of computational evidence support a deleterious effect; 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.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 requires a highly specific phenotype. No clinical phenotype details are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 (Supporting) requires a reputable source reporting the variant as pathogenic. ClinVar lists this variant as Likely Pathogenic, not Pathogenic, and no additional evidence is available. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 (Stand Alone) requires allele frequency >0.056% in gnomAD. The evidence shows 0% frequency. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 (Strong) requires allele frequency 0.0043%–0.056% in gnomAD. The evidence shows 0% frequency. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies if observed homozygous in healthy individuals. No such observations are reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires functional studies showing no damaging effect. Functional data show reduced activity. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation in multiple families. No segregation data exist. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 (Supporting) applies to missense variants in genes where only truncating variants cause disease. PTEN disease mechanism includes missense variants. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, BP2 requires observations in trans or multiple cis observations with other pathogenic variants. No such observations are reported. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to VCEP guidelines, BP3 applies to in-frame indels in repetitive regions. This is a missense variant. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 requires computational evidence suggesting no impact (REVEL <0.5). The evidence shows REVEL 0.96. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 requires an alternate molecular basis in a case. No such alternate basis is reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 (Supporting) requires reputable source reporting benign. No benign reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous or intronic variants with no splicing impact. This is a missense variant. Therefore, this criterion is not applied.