Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_004360.5(CDH1):c.2474dup (p.Pro826fs)

CA658658499

481178 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d92ac761-791e-4dbf-a19a-d7fd110fd456
Approved on: 2023-08-02
Published on: 2023-08-02

HGVS expressions

NM_004360.5:c.2474dup
NM_004360.5(CDH1):c.2474dup (p.Pro826fs)
NC_000016.10:g.68833324dup
CM000678.2:g.68833324dup
NC_000016.9:g.68867227dup
CM000678.1:g.68867227dup
NC_000016.8:g.67424728dup
NG_008021.1:g.101033dup
ENST00000261769.10:c.2474dup
ENST00000261769.9:c.2474dup
ENST00000422392.6:c.2291dup
ENST00000562118.1:n.692dup
ENST00000562836.5:n.2545dup
ENST00000566510.5:c.*1140dup
ENST00000566612.5:c.*714dup
ENST00000611625.4:c.2537dup
ENST00000612417.4:c.1854-867dup
ENST00000621016.4:c.1866-879dup
NM_004360.3:c.2474dup
NM_001317184.1:c.2291dup
NM_001317185.1:c.926dup
NM_001317186.1:c.509dup
NM_004360.4:c.2474dup
NM_001317184.2:c.2291dup
NM_001317185.2:c.926dup
NM_001317186.2:c.509dup

Pathogenic

Met criteria codes 4
PM5_Supporting PM2_Supporting PS4 PVS1_Strong
Not Met criteria codes 22
BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS3 PS1 PP4 PP1 PP3 PP2 PM6 PM3 PM1 PM4 BA1 BS4 BS3 BS1 BS2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
CDH1 VCEP
The NM_004360.5:c.2474dup (p.Pro826AlafsTer3) variant in CDH1 is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay. However, this truncated region (removes last 57 amino acids of the protein) is critical to protein function and located upstream the most 3' well-characterized pathogenic variant c.2506G>T (pGlu836Ter) (PVS1_Strong, PM5_Supporting; PMID: 29798843, ClinVar Variation ID: 479504). This variant is absent in gnomAD 2.1.1 (PM2_Supporting). This variant has been reported in 5 families meeting HDGC criteria (PS4; NCI hereditary gastric study, Ambry, Invitae). In summary, this variant meets the criteria to be classified as pathogenic for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PVS1_Strong, PS4, PM2_Supporting, PM5_Supporting. (CDH1 VCEP specifications version 3.1; 5/6/2022)
Met criteria codes
PM5_Supporting
This variant is located upstream of last known pathogenic truncating variant [c.2506G>T (p.Glu836Ter)] [PMID: 29798843, ClinVar Variation ID: 479504](PM5_Supporting).
PM2_Supporting
This variant is absent in gnomAD 2.1.1 (PM2_Supporting).
PS4
This variant has been reported in 5 families meeting HDGC criteria (PS4; NCI hereditary gastric study, Ambry, Invitae).
PVS1_Strong
The NM_004360.5:c.2474dup (p.Pro826AlafsTer3) variant in CDH1 is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay. However, this truncated region (removes last 57 amino acids of the protein) is critical to protein function and located upstream the most 3' well-characterized pathogenic variant c.2506G>T (pGlu836Ter) (PVS1_Strong; PMID: 29798843).
Not Met criteria codes
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
PS2
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
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
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
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
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
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
Observed in one unaffected female in her 30s. Family history of breast cancer (NOS) in the proband's mother (dx 40s).
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