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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

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

CA10580104

233979 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8ce34bc3-a1c5-4a8f-b0a7-bacacf8a921a
Approved on: 2023-08-24
Published on: 2023-08-24

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 4
PP1 PS4_Moderate PM5_Supporting PVS1_Strong
Not Met criteria codes 22
PS1 PS2 PS3 BP5 BP7 BP4 BP3 BP1 BP2 PP2 PP3 PP4 PM1 PM3 PM4 BA1 PM6 PM2 BS1 BS4 BS3 BS2

Evidence Links 9

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.1137+1G>A variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). 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 (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PS4_Moderate, PM5_Supporting and PP1.
Met criteria codes
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).
Review article PubMed:20233471
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
Review article PubMed:20373070
Review article PubMed:19725995
Review article PubMed:11665720
One family meeting HDGC clinical criteria PubMed:10477433
Review article PubMed:16997156
Review article PubMed:12647996
PM5_Supporting
Apply PM5_Supporting to the variant with the alteration at canonical splicing site.
PVS1_Strong
Canonical +1 donor splice site variant in intron 8 predicted to result in a truncated or absent protein
Not Met criteria codes
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
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
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
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
PM4
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
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.
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
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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