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]
Link to SEPIO compliant JSON-LD document

Variant: NM_004360.4(CDH1):c.2440-2A>G

CA396471928

496817 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d267b99c-f366-4e90-91ca-7e4ac610cf6f
Approved on: 2023-08-30
Published on: 2023-08-30

HGVS expressions

NM_004360.4:c.2440-2A>G
NM_004360.4(CDH1):c.2440-2A>G
NC_000016.10:g.68833288A>G
CM000678.2:g.68833288A>G
NC_000016.9:g.68867191A>G
CM000678.1:g.68867191A>G
NC_000016.8:g.67424692A>G
NG_008021.1:g.100997A>G
ENST00000261769.10:c.2440-2A>G
ENST00000261769.9:c.2440-2A>G
ENST00000422392.6:c.2257-2A>G
ENST00000562118.1:n.658-2A>G
ENST00000562836.5:n.2511-2A>G
ENST00000566510.5:c.*1106-2A>G
ENST00000566612.5:c.*680-2A>G
ENST00000611625.4:c.2503-2A>G
ENST00000612417.4:c.1854-903A>G
ENST00000621016.4:c.1866-915A>G
NM_004360.3:c.2440-2A>G
NM_001317184.1:c.2257-2A>G
NM_001317185.1:c.892-2A>G
NM_001317186.1:c.475-2A>G
NM_004360.5:c.2440-2A>G
NM_001317184.2:c.2257-2A>G
NM_001317185.2:c.892-2A>G
NM_001317186.2:c.475-2A>G
NM_004360.5(CDH1):c.2440-2A>G

Likely Pathogenic

Met criteria codes 4
PVS1_Strong PM5_Supporting PM2_Supporting PS3_Supporting
Not Met criteria codes 22
BP7 BP5 BP3 BP2 BP4 BP1 PS1 PS2 PS4 PM4 PM3 PM1 PM6 PP3 PP2 PP1 PP4 BA1 BS2 BS3 BS4 BS1

Evidence Links 1

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.2440-2A>G variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is also an RNA assay demonstrating abnormal splicing (PS3_Moderate; SCV000700319.2). In summary, this variant meets criteria to be classified as 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, PM2_Supporting, PS3_Moderate, PM5_Supporting.
Met criteria codes
PVS1_Strong
As per CDH1 ClinGen guidelines, PVS1_strong is invoked for canonical splice variants. This site is invariant in all transcripts. Predicted exon 16 skipping (last exon), leading to loss of the last 69 aa residues, p.(Asn814_Asp882del), which accounts for ~7.8% of protein. Most 3' pathogenic variant is c.2506G>T p.(Glu836*). No other variants at this position are recorded in ClinVar.
PM5_Supporting
Apply PM5_Supporting to the variant with the alteration at canonical splicing site.
PM2_Supporting
Not observed in population databases.
PS3_Supporting
SCV000700319.2 Ambry - RNA studies show abnormal splicing resulting in out-of-frame transcript. To avoid overweighting the evidence toward pathogenicity, VCEP recommended downgrading PS3 to PS3_Moderate.
Not Met criteria codes
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
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
PS1
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
PS4
Ambry Genetics - SCV000700319.2; PMID: 29798843 - Identified in one individual with lobular breast cancer in her 40s and no family history. Both probands do not meet the criteria for HDGC.
Identified in one individual with lobular breast cancer in her 40s and no family history (does not meet the criteria for HDGC, van der Post et al, J Med Genet (2015) 52(6):361-74) PubMed:29798843
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
PM6
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
PP1
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
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
BS3
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
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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.