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.634+5G>C

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA645509438

427623 (ClinVar)

Gene: PTEN

Condition: PTEN hamartoma tumor syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: bb8a0b6c-784c-4603-88f5-dc7102811034

Approved on: 2023-12-01

Published on: 2023-12-18

HGVS expressions

NM_000314.6:c.634+5G>C

NM_000314.6(PTEN):c.634+5G>C

NC_000010.11:g.87952264G>C

CM000672.2:g.87952264G>C

NC_000010.10:g.89712021G>C

CM000672.1:g.89712021G>C

NC_000010.9:g.89702001G>C

NG_007466.2:g.93826G>C

ENST00000686459.1:c.*220+5G>C

ENST00000688158.1:c.*745+5G>C

ENST00000688308.1:c.634+5G>C

ENST00000688922.1:c.555+5G>C

ENST00000693560.1:c.1153+5G>C

ENST00000371953.8:c.634+5G>C

ENST00000371953.7:c.634+5G>C

ENST00000472832.2:c.61+5G>C

NM_000314.5:c.634+5G>C

NM_001304717.2:c.1153+5G>C

NM_001304718.1:c.43+5G>C

NM_000314.7:c.634+5G>C

NM_001304717.5:c.1153+5G>C

NM_001304718.2:c.43+5G>C

NM_000314.8:c.634+5G>C

NM_000314.8(PTEN):c.634+5G>C

Pathogenic

PS3 PS1 PM2_Supporting PS4_Supporting

PS2 BA1 PM6 PM3 PM1 PM4 PM5 PP4 PP1 PP3 PP2 PVS1 BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP4 BP1

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

PTEN c.634+5G>C (IVS6+5G>C) meets criteria to be classified as 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). PS1: different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant. PS3: RNA, mini-gene, or other assay shows impact on splicing. (PMID 28677221). PM2_P: Absent in gnomAD (PMID 27535533). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 28677221).

PS3

RNA assay shows impact on splicing. Variant shown to cause exon 6 skipping in pt cells (PMID: 28677221).

Variant shown to cause exon 6 skipping in pt cells. PubMed:28677221

PS1

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant. Boccone et al. 2007 (PMID18080326) reported on a 6yo male carrying c.634+5G>A variant with BRRS, presumed de novo but parentage not confirmed. Proband specificity score = 8. In addition, c.634+5G>A is considered pathogenic in ClinVar. The splice impact for c.634+5G>A is the same but a bit less than it is for c.634+5G>C (Internal laboratory contributor). Therefore, PTEN-VCEP agreed with applying PS1 to c.634+5G>C variant.

PM2_Supporting

Absent in gnomAD.

PS4_Supporting

Proband specificity score is 1-1.5 (PMID 2867721).

Authors report that a subject with IVS6+5G>C was excluded from their study. No further details provided. PubMed:21659347

Found in pt 37, 45yo with CC score = 68. Pers hx macrocephaly, thyroid cancer, LDD, benign thyroid disease, hamartomatous polyps, lipomas, fibromas, acral keratoses, mucosal lesions. Recalculation CC score without more details score still >30, 1 phenotype point. PubMed:28677221

PS2