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

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
PVS1_Strong
Variant in intron 6 canonical splice acceptor site. Splicing aberration expected to cause a frameshift, and transcript expected to undergo NMD.
PM5_Supporting
Apply PM5_Supporting to the variant with the alteration at canonical splicing site.
PS3_Supporting
Splicing aberration resulting in a frame shift identified in patient's RNA (r.833-79_833-1ins; PMID: 22118538, 20624523).

PS4_Moderate
At least two families fulfilling HDGC clinical criteria (PMID: 22118538, 18391748, 21424370, 20624523). Another family from internal laboratory meets HDGC clinical criteria.

PM2_Supporting
Absent in gnomAD
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.

Not Met criteria codes
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
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
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
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
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
BA1
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
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
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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