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_004360.4(CDH1):c.2440-2A>G

CA396471928

496817 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: d267b99c-f366-4e90-91ca-7e4ac610cf6f

Approved on: 2023-08-30

Published on: 2023-08-30

HGVS expressions

NM_004360.4:c.2440-2A>G

NM_004360.4(CDH1):c.2440-2A>G

NC_000016.10:g.68833288A>G

CM000678.2:g.68833288A>G

NC_000016.9:g.68867191A>G

CM000678.1:g.68867191A>G

NC_000016.8:g.67424692A>G

NG_008021.1:g.100997A>G

ENST00000261769.10:c.2440-2A>G

ENST00000261769.9:c.2440-2A>G

ENST00000422392.6:c.2257-2A>G

ENST00000562118.1:n.658-2A>G

ENST00000562836.5:n.2511-2A>G

ENST00000566510.5:c.*1106-2A>G

ENST00000566612.5:c.*680-2A>G

ENST00000611625.4:c.2503-2A>G

ENST00000612417.4:c.1854-903A>G

ENST00000621016.4:c.1866-915A>G

NM_004360.3:c.2440-2A>G

NM_001317184.1:c.2257-2A>G

NM_001317185.1:c.892-2A>G

NM_001317186.1:c.475-2A>G

NM_004360.5:c.2440-2A>G

NM_001317184.2:c.2257-2A>G

NM_001317185.2:c.892-2A>G

NM_001317186.2:c.475-2A>G

NM_004360.5(CDH1):c.2440-2A>G

Likely Pathogenic

PM5_Supporting PM2_Supporting PS3_Supporting PVS1_Strong

BS3 BS4 BS1 BS2 BP7 BP5 BP3 BP2 BP4 BP1 PS1 PS2 PS4 BA1 PP3 PP2 PP1 PP4 PM6 PM4 PM3 PM1

Evidence Links 1

Expert Panel

CDH1 VCEP

Criteria Specification Information

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

CDH1 VCEP

The c.2440-2A>G variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is also an RNA assay demonstrating abnormal splicing (PS3_Moderate; SCV000700319.2). In summary, this variant meets criteria to be classified as likely 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, PS3_Moderate, PM5_Supporting.

PM5_Supporting

Apply PM5_Supporting to the variant with the alteration at canonical splicing site.

PM2_Supporting

Not observed in population databases.

PS3_Supporting

SCV000700319.2 Ambry - RNA studies show abnormal splicing resulting in out-of-frame transcript. To avoid overweighting the evidence toward pathogenicity, VCEP recommended downgrading PS3 to PS3_Moderate.

PVS1_Strong

As per CDH1 ClinGen guidelines, PVS1_strong is invoked for canonical splice variants. This site is invariant in all transcripts. Predicted exon 16 skipping (last exon), leading to loss of the last 69 aa residues, p.(Asn814_Asp882del), which accounts for ~7.8% of protein. Most 3' pathogenic variant is c.2506G>T p.(Glu836*). No other variants at this position are recorded in ClinVar.

BS3