Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000314.8(PTEN):c.46T>C (p.Tyr16His)

CA377781939

428195 (ClinVar)

Gene: PTEN

Condition: PTEN hamartoma tumor syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 85c0b2bd-3660-41c0-9b70-ac48995f56fb

HGVS expressions

NM_000314.8:c.46T>C

NM_000314.8(PTEN):c.46T>C (p.Tyr16His)

NC_000010.11:g.87864515T>C

CM000672.2:g.87864515T>C

NC_000010.10:g.89624272T>C

CM000672.1:g.89624272T>C

NC_000010.9:g.89614252T>C

NG_007466.2:g.6077T>C

NG_033079.1:g.3923A>G

ENST00000686459.1:c.46T>C

ENST00000688158.1:c.46T>C

ENST00000688308.1:c.46T>C

ENST00000693560.1:c.565T>C

ENST00000371953.8:c.46T>C

ENST00000371953.7:c.46T>C

ENST00000462694.1:n.48T>C

ENST00000487939.1:n.67T>C

ENST00000610634.1:c.-57T>C

ENST00000618586.1:n.15T>C

NM_000314.5:c.46T>C

NM_000314.6:c.46T>C

NM_001304717.2:c.565T>C

NM_001304718.1:c.-660T>C

NM_000314.7:c.46T>C

NM_001304717.5:c.565T>C

NM_001304718.2:c.-660T>C

Uncertain Significance

PM2_Supporting BS3_Supporting PP3 PP2

BA1 PVS1 BS1 BP7 BP4 PS3 PS1 PM1 PM5

Evidence Links 2

Expert Panel

PTEN VCEP

Criteria Specification Information

Criteria Specification: ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

PTEN VCEP

NM_000314.8(PTEN):c.46T>C (p.Tyr16His) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM2_P: This variant is absent from gnomAD database. PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PP3: REVEL score > 0.7 (score of this variant = 0.866) BS3_P: Well-established functional studies show no deleterious effect: Phosphatase activity >0 (score of this variant = 0.34095) per Mighell et al. 2018 (PMID: 29706350). Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign supporting and 3 pathogenic supporting codes get -1 + (1*3) points; total is 2 (Uncertain significance).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2).

BS3_Supporting

Well-established functional studies show no deleterious effect: Phosphatase activity >0 (score of this variant = 0.34095) per Mighell et al. 2018 (PMID: 29706350).

PIP3 phosphatase activity assays in yeast showed no obvious differences of PTEN PIP3-phosphatase activity between wildtype and p.Tyr16His variant. Cum_socre: 0.34095 PubMed:29706350

The cellular locations of PTEN protein in COS-7 cell assay and PIP3 phosphatase activity assays in yeast showed no obvious differences of PTEN PIP3-phosphatase activity between wildtype and p.Tyr16His variant. PubMed:29706633

PP3

REVEL score > 0.7 (score of this variant = 0.866)

PP2

PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PVS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP7

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP4

No splicing impact predicted. Should consider this variant as a missense.

PS3

Studies shows no obvious damaging effect on protein function

PS1

No same amino acid change as a previously established pathogenic variant

PM1

Not a residue in catalytic motifs.

PM5

BLOSUM62 score (2) is higher than [NM_000314.8(PTEN):c.46T>G (p.Tyr16Asp), Likely Pathogenic (ClinVar), BLOSUM62 score=-3]

Approved on: 2023-10-11

Published on: 2023-10-17

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.