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]
  • See Evidence submitted by expert panel for details.

Variant: NM_004360.4(CDH1):c.1137+1G>A

CA10580104

233979 (ClinVar)

Gene: CDH1
Condition: hereditary diffuse gastric cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8ce34bc3-a1c5-4a8f-b0a7-bacacf8a921a
Approved on: 2019-08-20
Published on: 2019-09-11

HGVS expressions

NM_004360.4:c.1137+1G>A
NM_004360.4(CDH1):c.1137+1G>A
NC_000016.10:g.68812264G>A
CM000678.2:g.68812264G>A
NC_000016.9:g.68846167G>A
CM000678.1:g.68846167G>A
NC_000016.8:g.67403668G>A
NG_008021.1:g.79973G>A
ENST00000261769.10:c.1137+1G>A
ENST00000261769.9:c.1137+1G>A
ENST00000422392.6:c.1137+1G>A
ENST00000562836.5:n.1208+1G>A
ENST00000565810.1:n.181+1G>A
ENST00000566510.5:c.981+1G>A
ENST00000566612.5:c.1137+1G>A
ENST00000611625.4:c.1137+1G>A
ENST00000612417.4:c.1137+1G>A
ENST00000621016.4:c.1137+1G>A
NM_004360.3:c.1137+1G>A
NM_001317184.1:c.1137+1G>A
NM_001317185.1:c.-479+1G>A
NM_001317186.1:c.-683+1G>A
NM_004360.5:c.1137+1G>A
NM_001317184.2:c.1137+1G>A
NM_001317185.2:c.-479+1G>A
NM_001317186.2:c.-683+1G>A
More

Likely Pathogenic

Met criteria codes 3
PVS1_Strong PP1 PS4_Moderate
Not Met criteria codes 23
BA1 BS2 BS1 BS4 BS3 BP4 BP3 BP1 BP2 BP5 BP7 PS1 PS2 PS3 PP2 PP3 PP4 PM1 PM3 PM5 PM4 PM6 PM2

Evidence Links 9

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
CDH1 VCEP
The c.1137+1G>A variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong). This variant is present in <1/100,000 alleles in the gnomAD cohort, however it is present in >1/50,000 alleles in the African sub-population (http://gnomad.broadinstitute.org). This variant was found to co-segregate with disease in multiple affected family members, with 3 meioses observed in one family (PP1; PMID: 10477433). This variant has also been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 28195815, 10477433). 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: PVS1_Strong, PS4_Moderate, and PP1.
Met criteria codes
PVS1_Strong
Canonical +1 donor splice site variant in intron 8 predicted to result in a truncated or absent protein
PP1
Co-segregates with diffuse gastric cancer over 3 meioses in one family that fulfils the clinical HDGC criteria (PMID: 10477433).
Co-segregates with diffuse gastric cancer over 3 meisoses PubMed:10477433
PS4_Moderate
Two families meeting HDGC clinical criteria (PMID: 28195815, 10477433). Two unrelated probands do not meeting HDGC criteria (SCV000568305.3). One proband pathology unknown (SCV000278454.5). Seven unrelated probands do not meet HDGC criteria (SCV000288420.3).
One family meeting HDGC clinical criteria PubMed:10477433
Review article PubMed:20233471
Review article PubMed:16997156
Review article PubMed:20373070
Review article PubMed:11665720
Review article PubMed:12647996
Review article PubMed:19725995
Proband age 35 years with multifocal, high-grade invasive adenocarcinoma, of signet-ring cell/diffuse type. Breast with atypical lobular hyperplasia and lobular carcinoma in situ with no evidence of malignancy. PubMed:28195815
Unaffected proband age unknown with a family history of ovarian cancer PubMed:30264118
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
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
Co-segregates with diffuse gastric cancer over 3 meisoses PubMed:10477433
BS3
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
BP3
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
BP2
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
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
PS3
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
PP3
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
PM1
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
PM5
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
PM2
Variant is present in gnomAD at <1/100,000 alleles (2/277,198 total). However, it is >1/50,000 alleles in the African sub-population (2/24,028). Thus, criterion is not met.
Curation History
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