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.80A>G (p.Tyr27Cys)

CA16613238

404160 (ClinVar)

Gene: PTEN

Condition: PTEN hamartoma tumor syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: d78c91f0-0265-4f61-9c40-6a7bc3309acb

HGVS expressions

NM_000314.8:c.80A>G

NM_000314.8(PTEN):c.80A>G (p.Tyr27Cys)

NC_000010.11:g.87894025A>G

CM000672.2:g.87894025A>G

NC_000010.10:g.89653782A>G

CM000672.1:g.89653782A>G

NC_000010.9:g.89643762A>G

NG_007466.2:g.35587A>G

ENST00000686459.1:c.80A>G

ENST00000688158.1:c.*275+13587A>G

ENST00000688308.1:c.80A>G

ENST00000693560.1:c.599A>G

ENST00000371953.8:c.80A>G

ENST00000371953.7:c.80A>G

ENST00000462694.1:n.82A>G

ENST00000610634.1:c.-23A>G

NM_000314.5:c.80A>G

NM_000314.6:c.80A>G

NM_001304717.2:c.599A>G

NM_001304718.1:c.-626A>G

NM_000314.7:c.80A>G

NM_001304717.5:c.599A>G

NM_001304718.2:c.-626A>G

Likely Pathogenic

PS3_Moderate PP3 PP2 PM6_Strong PM2_Supporting

BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS1 PP1 PP4 PVS1 PM3 PM1 PM4 PM5 BA1 BS2 BS4 BS3 BS1

Evidence Links 3

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.80A>G (p.Tyr27Cys) meets criteria to be classified as likely pathogenic 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). PM6_S: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history in a proband(s) with phenotype specificity score of 1-1.5 (PMID: 24375884). PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.648 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PM2_P: Absent in large sequenced populations (PMID: 27535533). 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 = 0.991)

PS3_Moderate

Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.648 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). Note: discussed with team, decided to not apply criteria to Mingo given lack of positive control. Mighell et al (2018): High confidence variant, cum_score = -1.648

Low (score 0.35) protein abundance PubMed:29785012

Hypomorphic score -1.65. Score now below threshold (-1.11) for application of PS3_Moderate evidence per updated assessment guidelines. PubMed:29706350

Study appears to show loss of phosphatase activity and protein localization in nucleus or nucleus/cytoplasm. However, no positive control provided. PubMed:29706633

PP3

REVEL score > 0.7 (score of this variant = 0.991)

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.

PM6_Strong

One proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype. (PMID: 24375884) Vanderver 2014 (PMID: 24375884): Per v3 guidelines (released 3/27/23), can bump PM6 to PM6_S for de novo occurrence with highly specific phenotype (meets criteria to count towards PS4).

PM2_Supporting

Absent in gnomAD

BP2