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.833-2A>G

CA396459533

439045 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: a2223df7-8e99-49a0-b892-919ff9299d5e
Approved on: 2023-08-28
Published on: 2023-08-28

HGVS expressions

NM_004360.5:c.833-2A>G
NM_004360.5(CDH1):c.833-2A>G
NC_000016.10:g.68811682A>G
CM000678.2:g.68811682A>G
NC_000016.9:g.68845585A>G
CM000678.1:g.68845585A>G
NC_000016.8:g.67403086A>G
NG_008021.1:g.79391A>G
ENST00000261769.10:c.833-2A>G
ENST00000261769.9:c.833-2A>G
ENST00000422392.6:c.833-2A>G
ENST00000561751.1:n.455-2A>G
ENST00000562836.5:n.904-2A>G
ENST00000566510.5:c.677-2A>G
ENST00000566612.5:c.833-2A>G
ENST00000611625.4:c.833-2A>G
ENST00000612417.4:c.833-2A>G
ENST00000621016.4:c.833-2A>G
NM_004360.3:c.833-2A>G
NM_001317184.1:c.833-2A>G
NM_001317185.1:c.-783-2A>G
NM_001317186.1:c.-987-2A>G
NM_004360.4:c.833-2A>G
NM_001317184.2:c.833-2A>G
NM_001317185.2:c.-783-2A>G
NM_001317186.2:c.-987-2A>G
More

Pathogenic

Met criteria codes 6
PP1_Moderate PVS1_Strong PS3_Supporting PM2_Supporting PS4_Moderate PM5_Supporting
Not Met criteria codes 20
BA1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS1 PP4 PP3 PP2 PM6 PM3 PM1 PM4

Evidence Links 7

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.833-2A>G variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). There is multiple RNA assays demonstrating abnormal out-of-frame transcript for this variant (PS3_Supporting; PMID: 22118538, 20624523). The variant is absent in the gnomAD cohort. (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 3 families meeting HDGC clinical criteria (PS4_Moderate; PMID: 22118538, 18391748, 21424370, 20624523, internal laboratory contributor). This variant was found to co-segregate with disease in multiple affected family members, with 5 meioses observed over two families (PP1_Moderate; PMID: 20624523, internal laboratory contributor). Therefore, 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_Strong, PS3_Supporting, PM2_Supporting, PS4_Moderate, PP1_Moderate, PM5_Supporting.
Met criteria codes
PP1_Moderate
Total 5 informative meioses: Variant segregates with gastric cancer across 3 meioses in one HDGC family (PMID: 20624523). 2 informative meioses from internal laboratory.
Variant segregates in a large HDGC kindred. Two confirmed carriers diagnosed with gastric cancer, and two obligate carriers diagnosed with gastric cancer. PubMed:20624523
PVS1_Strong
Variant in intron 6 canonical splice acceptor site. Splicing aberration expected to cause a frameshift, and transcript expected to undergo NMD.
PS3_Supporting
Splicing aberration resulting in a frame shift identified in patient's RNA (r.833-79_833-1ins; PMID: 22118538, 20624523).
RT-PCR of patient's RNA demonstrates that the variant deactivates the wild-type acceptor site and leads to activation of a cryptic acceptor site within intron 6, causing the insertion of a 79-bp intronic sequence between exon 6 and 7 (r.833-79_833-1ins), and resulting in a frame shift. PubMed:22118538
RT-PCR of patient and healthy control RNA. Activation of a cryptic splice site leading to inclusion of the final 79 bp of intron 6 within the transcript identified in the patient RNA only. PubMed:20624523
PM2_Supporting
Absent in gnomAD
PS4_Moderate
At least two families fulfilling HDGC clinical criteria (PMID: 22118538, 18391748, 21424370, 20624523). Another family from internal laboratory meets HDGC clinical criteria.
Review article referencing the report of the variant in Rogers et al 2008 PubMed:20373070
Korean patient diagnosed with signet ring cell carcinoma at 27 years. Both father and uncle died of stomach cancer (histological diagnosis unknown) at 33 and 41 years, respectively. PubMed:22118538
Review article in German PubMed:20824432
Same proband as Rogers et al 2008 PubMed:21424370
References the report of the variant in Rogers et al 2008 PubMed:22225527
Same proband as Rogers et al 2008 PubMed:20624523
Variant identified in a male age 52 from the USA, diagnosed with diffuse gastric cancer. From a family fullfilling HDGC clinical criteria. PubMed:18391748
PM5_Supporting
Apply PM5_Supporting to the variant with the alteration at canonical splicing site.
Not Met criteria codes
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
Variant segregates in a large HDGC kindred. Two confirmed carriers diagnosed with gastric cancer, and two obligate carriers diagnosed with gastric cancer. PubMed:20624523
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
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
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
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
Curation History
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