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_004360.4(CDH1):c.532-1G>C

Curation Version - 3.0
Curation History
JSON LD for Version 3.0

CA8129891

406644 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 178322a8-a2f1-4290-9b3a-886e742bd5fa

Approved on: 2024-03-25

Published on: 2024-03-27

HGVS expressions

NM_004360.4:c.532-1G>C

NM_004360.4(CDH1):c.532-1G>C

NC_000016.10:g.68808692G>C

CM000678.2:g.68808692G>C

NC_000016.9:g.68842595G>C

CM000678.1:g.68842595G>C

NC_000016.8:g.67400096G>C

NG_008021.1:g.76401G>C

ENST00000261769.10:c.532-1G>C

ENST00000261769.9:c.532-1G>C

ENST00000422392.6:c.532-1G>C

ENST00000561751.1:c.299-1G>C

ENST00000562836.5:n.603-1G>C

ENST00000564676.5:n.814-1G>C

ENST00000564745.1:n.527-1G>C

ENST00000566510.5:c.531+125G>C

ENST00000566612.5:c.532-1G>C

ENST00000567320.1:n.42-1G>C

ENST00000611625.4:c.532-1G>C

ENST00000612417.4:c.532-1G>C

ENST00000621016.4:c.532-1G>C

NM_004360.3:c.532-1G>C

NM_001317184.1:c.532-1G>C

NM_001317185.1:c.-1084-1G>C

NM_001317186.1:c.-1288-1G>C

NM_004360.5:c.532-1G>C

NM_001317184.2:c.532-1G>C

NM_001317185.2:c.-1084-1G>C

NM_001317186.2:c.-1288-1G>C

NM_004360.5(CDH1):c.532-1G>C

Pathogenic

PS3 PS4 PVS1_Strong PM5_Supporting PM2_Supporting

PS2 PM6 BA1 BS2 BS3 BS1

Evidence Links 0

Expert Panel

CDH1 VCEP

Criteria Specification Information

Criteria Specification: ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

CDH1 VCEP

The c.532-1G>C variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). This variant is present once (1/245,906 alleles) in the gnomAD v2 cohort (PM2_Supporting; http://gnomad.broadinstitute.org). Additionally, this variant has been reported in six families meeting HDGC clinical criteria (PS4; internal laboratory data). RNA analysis demonstrated that this variant results in an out-of-frame transcript, r.532_547del p.(I178Tfs*32) (PS3; internal laboratory data). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PS4, PS3, PM5_Supporting.

PS3

RNA analysis suggests this variant results in an out-of-frame transcript (r.532_547del p.I178Tfs*32, Ambry).

PS4

The variant has been observed in six families meeting IGCLC criteria for HDGC (Invitae, NCI, GeneDx). Eight additional families with DGC and/or LBC but who do not meet criteria for HDGC have also been observed (Invitae, Ambry, NCI).

PVS1_Strong

Canonical -1 splice site variant in intron 4, predicted to result in a truncated or absent protein. No predicted cryptic splice sites nearby.

PM5_Supporting

Application as indicated by the CDH1 splice site decision tree for variants upstream of the most 3' pathogenic variant.

PM2_Supporting

This variant occurs at a maximum subpopulation frequency of 0.00006 (1 of 16,124 alleles) in the African subpopulation and 0.000001591 (1 in 628,718 alleles) in the gnomAD v4.0.0 database.

PS2

The variant has not been observed de novo.

PM6

The variant has not been observed de novo.

BA1

This variant occurs at a maximum subpopulation frequency of 0.00006 (1 of 16,124 alleles) in the African subpopulation and 0.000001591 (1 in 628,718 alleles) in the gnomAD v4.0.0 database.

BS2

BS3

RNA analysis suggests this variant results in an out-of-frame transcript (r.532_547del p.I178Tfs*32, Ambry).

BS1

This variant occurs at a maximum subpopulation frequency of 0.00006 (1 of 16,124 alleles) in the African subpopulation and 0.000001591 (1 in 628,718 alleles) in the gnomAD v4.0.0 database.

Curation History

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