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

CA288040

127915 (ClinVar)

Gene: CDH1

Condition: hereditary diffuse gastric cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 3d5bfeed-bb3f-464f-8dd0-b78a9395290e

Approved on: 2021-05-04

Published on: 2021-05-04

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 PS4 PP1_Strong PS3_Moderate PVS1_Strong

• Not Met criteria codes: BS1 BS4 BS3 BS2 BP5 BP7 BP4 BP3 BP1 BP2 PS1 PS2 PP2 PP3 PP4 PM6 PM1 PM3 PM5 PM4 BA1

Expert Panel

Criteria Specification Information

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): PVS1_Strong, PS4, PP1_Strong, PS3_Moderate, PM2_Supporting.

Met criteria codes

• 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.
• PP1_Strong: 9 meioses across 5 families (GeneDx, NCI)
• PS3_Moderate: Multiple aberrant transcripts expected to lead to truncated protein, and account for ~40% of overall allele fraction (PMID: 31843900).
• 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

Not Met criteria codes

• 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
• 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.
• PM6: 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
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: 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