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]

Variant: NM_004360.5(CDH1):c.2490dup (p.Leu831fs)

CA645369680

428634 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: ca83e0ad-0e8b-41ff-8d99-af004bc407b9
Approved on: 2023-08-30
Published on: 2023-08-30

HGVS expressions

NM_004360.5:c.2490dup
NM_004360.5(CDH1):c.2490dup (p.Leu831fs)
NC_000016.10:g.68833340dup
CM000678.2:g.68833340dup
NC_000016.9:g.68867243dup
CM000678.1:g.68867243dup
NC_000016.8:g.67424744dup
NG_008021.1:g.101049dup
ENST00000261769.10:c.2490dup
ENST00000261769.9:c.2490dup
ENST00000422392.6:c.2307dup
ENST00000562118.1:n.708dup
ENST00000562836.5:n.2561dup
ENST00000566510.5:c.*1156dup
ENST00000566612.5:c.*730dup
ENST00000611625.4:c.2553dup
ENST00000612417.4:c.1854-851dup
ENST00000621016.4:c.1866-863dup
NM_004360.3:c.2490dup
NM_001317184.1:c.2307dup
NM_001317185.1:c.942dup
NM_001317186.1:c.525dup
NM_004360.4:c.2490dup
NM_001317184.2:c.2307dup
NM_001317185.2:c.942dup
NM_001317186.2:c.525dup
More

Likely Pathogenic

Met criteria codes 4
PVS1_Strong PM2_Supporting PM5_Supporting PS4_Supporting
Not Met criteria codes 22
PM6 PM3 PM1 PM4 BA1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP4 BP1 BP3 PS2 PS1 PS3 PP4 PP1 PP3 PP2

Evidence Links 0

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.2490dupG (p.Leu831AlafsTer4) variant results in a premature stop codon that leads to a truncated protein. It is located within the nonsense mediated decay resistant zone, and upstream of codon 836 where the most 3' pathogenic variant in CDH1 terminates (PVS1_Strong, PMID: 29798843). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in a family meeting HDGC criteria (PS4_Supporting; SCV000580713.3). In summary, the clinical significance of this variant is likely 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, Supporting, PM2_Supporting
Met criteria codes
PVS1_Strong
PTC created in exon 16/16 at position 834 (p.Leu831Alafs*4), which is located in the NMD-resistant zone located upstream of p.Glu836*
PM2_Supporting
Absent in gnomAD v2.1 and v3 in a region of sufficient coverage
PM5_Supporting
Not predict/prove to undergo NMD.
PS4_Supporting
1 family that meets HDGC criteria: 1 case of DGC diagnosed <40 years
Not Met criteria codes
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
BS2
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
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
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
BP3
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
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
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
Curation History
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