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]

Variant: NM_000314.6(PTEN):c.370T>C (p.Cys124Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA000422

7817 (ClinVar)

Gene: PTEN

Condition: PTEN hamartoma tumor syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b3d1af7f-63db-40b7-9bb6-1937661a6003

Approved on: 2019-06-25

Published on: 2019-07-23

HGVS expressions

NM_000314.6:c.370T>C

NM_000314.6(PTEN):c.370T>C (p.Cys124Arg)

NC_000010.11:g.87933129T>C

CM000672.2:g.87933129T>C

NC_000010.10:g.89692886T>C

CM000672.1:g.89692886T>C

NC_000010.9:g.89682866T>C

NG_007466.2:g.74691T>C

NM_000314.5:c.370T>C

NM_001304717.2:c.889T>C

NM_001304718.1:c.-381T>C

NM_000314.7:c.370T>C

NM_001304717.5:c.889T>C

NM_001304718.2:c.-381T>C

ENST00000371953.7:c.370T>C

ENST00000498703.1:n.196T>C

ENST00000610634.1:c.268T>C

Pathogenic

PS3 PM1 PM2 PP2 PM6_Strong PS4_Supporting

PS2 PS1 BA1 PM5 PM4 PP3 PP1 PVS1 BS3 BS1 BS4 BS2 BP7 BP5 BP4 BP2

Evidence Links 8

Expert Panel

PTEN VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

PTEN VCEP

PTEN c.370T>C (p.Cys124Arg) 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 (PMID 10866302, PMID 29706350) PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (internal laboratory contributor SCV000568254.4) 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 SCV000568254.4)

PS3

I agree (FH)

Knock-in mouse model; HOM mice embryonic lethal, HOM mouse fetuses displayed multiple anomalies. PS3 already applied for other literature. PubMed:20194734

Complete loss of phosphatase activity, similar to null. PubMed:10866302

Appears to show decreased stability (score 0.28) but EP still figuring out cutoff for this publication, and PS3 already applied for other literature. PubMed:29785012

Y2H assay, no interaction with LKB1. Not relevant for criteria. PubMed:15987703

Phosphatase activity in truncation-like range (-4.45) - PS3 applies per EP. PubMed:29706350

PM1

I Agree (FH)

PM2

absent gnomAD, good coverage. I agree (FH)

PP2

I agree (FH)

PM6_Strong

2 internal GDx cases (SCV000568254.4)

PS4_Supporting

1 internal GDx case (SCV000568254.4)

Reported in two families with "CS". Family 1.) Macrocephaly, benign findings of skin, thyroid, GI and breast Family 2.) Head size not documented, malignant and benign GI findings, benign findings thyroid, skin, and breast. Unsure which features present in which individuals, unable to apply criteria. PubMed:9467011

Identified in pt n130, female with macrocephaly, benign thyroid disease, and CS-related skin findings NOS. Minimum CC score = 11. PubMed:9259288

Same pt as Nelen 1997. PubMed:10234502

PS2