Variant: NM_004360.4(CDH1):c.1792C>T (p.Arg598Ter)

CA281000

12241 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 8d966550-3108-4786-8d4d-092988c239d6

Approved on: 2023-08-29

Published on: 2023-08-29

HGVS expressions

NM_004360.4:c.1792C>T
NM_004360.4(CDH1):c.1792C>T (p.Arg598Ter)
NC_000016.10:g.68822081C>T
CM000678.2:g.68822081C>T
NC_000016.9:g.68855984C>T
CM000678.1:g.68855984C>T
NC_000016.8:g.67413485C>T
NG_008021.1:g.89790C>T
ENST00000261769.10:c.1792C>T
ENST00000261769.9:c.1792C>T
ENST00000422392.6:c.1609C>T
ENST00000562836.5:n.1863C>T
ENST00000566510.5:c.*458C>T
ENST00000566612.5:c.*32C>T
ENST00000611625.4:c.1855C>T
ENST00000612417.4:c.1792C>T
ENST00000621016.4:c.1792C>T
NM_004360.3:c.1792C>T
NM_001317184.1:c.1609C>T
NM_001317185.1:c.244C>T
NM_001317186.1:c.-174C>T
NM_004360.5:c.1792C>T
NM_001317184.2:c.1609C>T
NM_001317185.2:c.244C>T
NM_001317186.2:c.-174C>T

Pathogenic

• Met criteria codes: PM5_Supporting PS2 PS4 PP1_Strong PM2_Supporting PVS1

• Not Met criteria codes: BA1 BS1 BS4 BS3 BS2 BP5 BP7 BP4 BP3 BP1 BP2 PS1 PS3 PP2 PP3 PP4 PM1 PM3 PM4 PM6

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.1792C>T (p.Arg598*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant was found to co-segregate with disease in multiple affected family members, with >7 meioses observed across at least two families (PP1_Strong; PMID: 21696387, 16061854, 11419427 and SCV000275702.5). This variant has also been reported in at least four families meeting HDGC clinical criteria (PS4_Strong; PMID: 9751616, 21696387, 16061854, 11419427). There is one known de novo observation of this variant with parental confirmation in a patient with diffuse gastric cancer and/or lobular breast cancer (PS2; PMID: 21696387). 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, PM2_Supporting, PP1_Strong, PS4, PS2, PM5_Supporting.

Met criteria codes

• PM5_Supporting: Apply PM5_Supporting to nonsense/frameshift variants that are predicted/proved to undergo NMD.
• PS2: Variant confirmed de novo in patient with gastric cancer. Daughter also had the variant and presented with gastric cancer. Maternity and Paternity confirmed.
• PS4: Multiple families with history of gastric cancer and multiple family members with the variant
• PP1_Strong: Four families (3 in literature one provided in excel sheet - SCV000275702.5) with multiple family members with the variant and with diffuse gastric cancer.
• PM2_Supporting: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Not Met criteria codes

• BA1: 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
• 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: Splicing models show disruption of an exonic ese site.
• 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
• PS3: 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: Splicing models show disruption of an exonic ese site.
• PP4: Multiple families with history of gastric cancer and multiple family members with the variant
• 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