The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]


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

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
NM_004360.5(CDH1):c.1792C>T (p.Arg598Ter)

Pathogenic

Met criteria codes 6
PM5_Supporting PVS1 PP1_Strong PM2_Supporting PS4 PS2
Not Met criteria codes 20
BA1 BP7 BP5 BP3 BP2 BP1 BP4 BS2 BS3 BS4 BS1 PP4 PP2 PP3 PM6 PM4 PM3 PM1 PS1 PS3

Evidence Links 4

Expert Panel

Criteria Specification Information

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
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.
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
PS4
Multiple families with history of gastric cancer and multiple family members with the variant

PS2
Variant confirmed de novo in patient with gastric cancer. Daughter also had the variant and presented with gastric cancer. Maternity and Paternity confirmed.
Not Met criteria codes
BA1
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
BP5
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
BP2
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
BP4
Splicing models show disruption of an exonic ese site.
BS2
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
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
Multiple families with history of gastric cancer and multiple family members with the variant
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.
PM6
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
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
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
Approved on: 2023-08-29
Published on: 2023-08-29
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.