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_004360.5(CDH1):c.1566-2A>G

CA396464772

463723 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: b1173f50-45dc-4a10-907f-e6adb5833323

HGVS expressions

NM_004360.5:c.1566-2A>G
NM_004360.5(CDH1):c.1566-2A>G
NC_000016.10:g.68819278A>G
CM000678.2:g.68819278A>G
NC_000016.9:g.68853181A>G
CM000678.1:g.68853181A>G
NC_000016.8:g.67410682A>G
NG_008021.1:g.86987A>G
ENST00000261769.10:c.1566-2A>G
ENST00000261769.9:c.1566-2A>G
ENST00000422392.6:c.1383-2A>G
ENST00000562836.5:n.1637-2A>G
ENST00000566510.5:c.*232-2A>G
ENST00000566612.5:c.1566-2723A>G
ENST00000611625.4:c.1629-2A>G
ENST00000612417.4:c.1566-2A>G
ENST00000621016.4:c.1566-2A>G
NM_004360.3:c.1566-2A>G
NM_001317184.1:c.1383-2A>G
NM_001317185.1:c.18-2A>G
NM_001317186.1:c.-254-2723A>G
NM_004360.4:c.1566-2A>G
NM_001317184.2:c.1383-2A>G
NM_001317185.2:c.18-2A>G
NM_001317186.2:c.-254-2723A>G

Uncertain Significance

Met criteria codes 3
PM2_Supporting PVS1_Moderate PS4_Supporting
Not Met criteria codes 23
BA1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS3 PS1 PP4 PP1 PP3 PP2 PM3 PM1 PM4 PM5 PM6

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.1566-2A>G variant is a canonical splice variant predicted to result in the use of a cryptic splice site which preserves the reading frame (PVS1_moderate). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in one individual meeting criteria for HDGC (PS4_supporting; PMID: 31841163). In summary, the clinical significance of this variant is classified as of uncertain significance based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_moderate, PS4_supporting, PM2_supporting.
Met criteria codes
PM2_Supporting
absent in gnomAD v2.1.1 and v3
PVS1_Moderate
Predicted in SpliceAI to result in the use of a cryptic splice site which leads to an in-frame inclusion of 7 amino acids, p.T522_Y523insNSLSPFG
PS4_Supporting
1 proband meeting individual criteria for HDGC (gastric in situ signet ring cells in individuals <50 years of age; SCV000637734.1)
Not Met criteria codes
BA1
absent in gnomAD v2.1.1 and v3
BS2
1 individual without HDGC (SCV000637734.1)
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
absent in gnomAD v2.1.1 and v3
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
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
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
PM5
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
Approved on: 2023-08-21
Published on: 2023-08-21
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