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]

Link to SEPIO compliant JSON-LD document

Variant: NM_004360.5(CDH1):c.1565+1G>C

CA16614968

406622 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 08051975-97cf-4ea2-ba42-18d87d4a1a4b

HGVS expressions

NM_004360.5:c.1565+1G>C

NM_004360.5(CDH1):c.1565+1G>C

NC_000016.10:g.68815760G>C

CM000678.2:g.68815760G>C

NC_000016.9:g.68849663G>C

CM000678.1:g.68849663G>C

NC_000016.8:g.67407164G>C

NG_008021.1:g.83469G>C

ENST00000261769.10:c.1565+1G>C

ENST00000261769.9:c.1565+1G>C

ENST00000422392.6:c.1382+1G>C

ENST00000562836.5:n.1636+1G>C

ENST00000566510.5:c.*231+1G>C

ENST00000566612.5:c.1565+1G>C

ENST00000611625.4:c.1628+1G>C

ENST00000612417.4:c.1565+1G>C

ENST00000621016.4:c.1565+1G>C

NM_004360.3:c.1565+1G>C

NM_001317184.1:c.1382+1G>C

NM_001317185.1:c.17+1G>C

NM_001317186.1:c.-255+1G>C

NM_004360.4:c.1565+1G>C

NM_001317184.2:c.1382+1G>C

NM_001317185.2:c.17+1G>C

NM_001317186.2:c.-255+1G>C

Pathogenic

PVS1_Strong PP1_Strong PM2_Supporting PS4 PM5_Supporting

PM6 PM1 PM3 PM4 BA1 BS2 BS3 BS4 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS1 PS3 PS2 PP4 PP3 PP2

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

CDH1 VCEP

The c.1565+1G>C variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least four families meeting HDGC clinical criteria (PS4; PMID: 26182300, SCV000545383.5 and internal laboratory contributor). This variant was also found to co-segregate with disease in multiple affected family members, with at least nine meioses observed across four families (PP1_Strong; SCV000545383.5, SCV000665081.3 and internal laboratory contributor). 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, PS4, PP1_Strong, PM2_Supporting, PM5_Supporting.

PVS1_Strong

Canonical +1 splice site in intron 10. Predicted by SpliceAI to abolish the native donor site and activate a cryptic donor 6 bp into the intron (creates PTC) or exon skipping. Both expected to lead to NMD

PP1_Strong

9 affected segregations over 4 families (Ambry, Invitae, NCI)

PM2_Supporting

Absent in gnomAD v2.1.1 and v3.0 in a region of sufficient coverage

PS4

At least 4 families that meet HDGC clinical criteria (NCI, Invitae, PMID: 26182300). 5 families with missing pathology or age of diagnosis information to meet clinical criteria.

PM5_Supporting

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

PM6