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]

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Variant: NM_000314.7(PTEN):c.367C>G (p.His123Asp)

CA377482278

428277 (ClinVar)

Gene: PTEN

Condition: PTEN hamartoma tumor syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 363d5223-feca-47e8-a3b8-115e05778f7f

Approved on: 2019-11-22

Published on: 2019-12-04

HGVS expressions

NM_000314.7:c.367C>G

NM_000314.7(PTEN):c.367C>G (p.His123Asp)

NC_000010.11:g.87933126C>G

CM000672.2:g.87933126C>G

NC_000010.10:g.89692883C>G

CM000672.1:g.89692883C>G

NC_000010.9:g.89682863C>G

NG_007466.2:g.74688C>G

NM_000314.5:c.367C>G

NM_000314.6:c.367C>G

NM_001304717.2:c.886C>G

NM_001304718.1:c.-384C>G

NM_001304717.5:c.886C>G

NM_001304718.2:c.-384C>G

ENST00000371953.7:c.367C>G

ENST00000498703.1:n.193C>G

ENST00000610634.1:c.265C>G

Pathogenic

PS3 PP2 PS4_Supporting PM1 PM2

Evidence Links 2

Expert Panel

PTEN VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

PTEN VCEP

PTEN c.367C>G (p.His123Asp) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3: Phosphatase activity <50% of wild type OR RNA, mini-gene, or other assay shows impact on splicing. (PMID 29706350, 21828076) PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel. PM2: 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. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor SCV000580072.3)

PS3

Comprehensive in vivo functional analysis of human PTEN using a heterologous yeast reconstitution system. Phosphatase activity was fully inactive (Rodríguez-Escudero I et al2011).

High-throughput functional assay testing PTEN lipid phosphatase activity score of -4.345802175 so this variant had truncation-like function and was 'TRUE'. PubMed:29706350

Comprehensive in vivo functional analysis of human PTEN using a heterologous yeast reconstitution system. Phosphatase activity was fully inactive. PubMed:21828076

PP2

Missense

PS4_Supporting

Teenager with fundic gland polyps diagnosed as a child with hamartomatous features, multiple lipomas, Hashimoto thyroiditis, right thigh hamartoma, macrocephaly, penile freckling. Pediatric CC score of 11 (1 point) (Ambry Genetics).

PM1

This amino acid position, 123, is in a catalytic motif.

PM2

Not present in gnomAD (coverage >90X).

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