The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries.
[Disclaimer]
- Gene obtained from curated document aligns with ClinVar but not with the Allele Registry data
Variant: NM_004360.5(CDH1):c.1565+1G>A
- Curation Version - 2.1
- Curation History
- JSON LD for Version 2.1
127915 (ClinVar)
Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
UUID: 3d5bfeed-bb3f-464f-8dd0-b78a9395290e
Approved on: 2023-08-30
Published on: 2023-08-30
HGVS expressions
NM_004360.5:c.1565+1G>A
NM_004360.5(CDH1):c.1565+1G>A
Pathogenic
Met criteria codes 6
PP1_Strong
PS4
PM5_Supporting
PVS1_Strong
PS3_Moderate
PM2_Supporting
Not Met criteria codes 20
BA1
PS1
PS2
PP3
PP2
PP4
PM3
PM1
PM4
PM6
BS2
BS3
BS4
BS1
BP2
BP3
BP4
BP1
BP5
BP7
Evidence Links 0
Evidence submitted by expert panel
CDH1 VCEP
The c.1565+1G>A variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least six families meeting HDGC clinical criteria (PS4; PMID: 26182300, SCV000149752.12 and internal laboratory contributor). This variant was also found to co-segregate with disease in multiple affected family members, with nine meioses observed across at least five families (PP1_Strong; SCV000149752.12 and internal laboratory contributor). The c.1565+1G>A allele was demonstrated to alter splicing through RNASeq analysis of mRNA from an affected carrier (PS3_Moderate; PMID: 31843900). 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, PS3_Moderate, PM2_Supporting.
Met criteria codes
At least 6 families meeting HDGC clinical criteria (PMID: 26182300, GeneDx, NCI). 10 families with insufficient evidence to meet criteria.
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
Multiple aberrant transcripts expected to lead to truncated protein, and account for ~40% of overall allele fraction (Table S2: cryptic splice, ins 6bp, codon 523 stop) (PMID: 31843900). To avoid overweighting the evidence toward pathogenicity, VCEP recommended downgrading PS3 to PS3_Moderate.
Not Met criteria codes
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
Proband with DGC dx at age 50s at testing and family history of breast cancer. Two families at Ambry Genetics Lab meeting clinical criteria. Total of 4 families.
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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