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

CA288040

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: 2023-08-25

Published on: 2023-08-25

HGVS expressions

NM_004360.5:c.1565+1G>A
NM_004360.5(CDH1):c.1565+1G>A
NC_000016.10:g.68815760G>A
CM000678.2:g.68815760G>A
NC_000016.9:g.68849663G>A
CM000678.1:g.68849663G>A
NC_000016.8:g.67407164G>A
NG_008021.1:g.83469G>A
ENST00000261769.10:c.1565+1G>A
ENST00000261769.9:c.1565+1G>A
ENST00000422392.6:c.1382+1G>A
ENST00000562836.5:n.1636+1G>A
ENST00000566510.5:c.*231+1G>A
ENST00000566612.5:c.1565+1G>A
ENST00000611625.4:c.1628+1G>A
ENST00000612417.4:c.1565+1G>A
ENST00000621016.4:c.1565+1G>A
NM_004360.3:c.1565+1G>A
NM_001317184.1:c.1382+1G>A
NM_001317185.1:c.17+1G>A
NM_001317186.1:c.-255+1G>A
NM_004360.4:c.1565+1G>A
NM_001317184.2:c.1382+1G>A
NM_001317185.2:c.17+1G>A
NM_001317186.2:c.-255+1G>A

Pathogenic

• Met criteria codes: PM2_Supporting PVS1_Strong PP1_Strong PM5_Supporting PS3 PS4

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

Expert Panel

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; 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, PM2_Supporting.

Met criteria codes

• PM2_Supporting: Absent in gnomAD v2.1.1 and gnomAD v3.1 in a region of sufficient coverage
• 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 meioses across 5 families (GeneDx, NCI)
• PM5_Supporting: Apply PM5_Supporting to the variant with the alteration at canonical splicing site.
• PS3: 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).
• 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

• PM1: 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
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: 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
• BS4: 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
• 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
• BP4: 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
• BP1: 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
• 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
• BA1: 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
• PP3: 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.