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

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: PM5_Supporting PS3_Moderate PP1_Strong PVS1_Strong PM2_Supporting PS4

• Not Met criteria codes: PM6 PM3 PM1 PM4 BA1 BS3 BS4 BS1 BS2 BP5 BP7 BP2 BP3 BP4 BP1 PS1 PS2 PP3 PP2 PP4

Expert Panel

CDH1 VCEP

Criteria Specification Information

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

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

• PM5_Supporting: Apply PM5_Supporting to the variant with the alteration at canonical splicing site.
• PS3_Moderate: 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.
• PP1_Strong: 9 meioses across 5 families (GeneDx, NCI)
• 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
• PM2_Supporting: Absent in gnomAD v2.1.1 and gnomAD v3.1 in a region of sufficient coverage
• PS4: At least 6 families meeting HDGC clinical criteria (PMID: 26182300, GeneDx, NCI). 10 families with insufficient evidence to meet criteria.

Not Met criteria codes

• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• 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
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: 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
• BP4: 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
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: 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.