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 ClinVar but not with the Allele Registry data

Variant: NM_004360.4(CDH1):c.832+1G>T

239914 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: ca8eb295-29b0-45b5-8879-6065cde6d70d
Approved on: 2023-08-29
Published on: 2023-08-29

HGVS expressions

NM_004360.4:c.832+1G>T
NM_004360.4(CDH1):c.832+1G>T
NM_004360.5(CDH1):c.832+1G>T

Pathogenic

Met criteria codes 4
PM2_Supporting PM5_Supporting PVS1_Strong PS4
Not Met criteria codes 22
PM3 PM1 PM4 PM6 BA1 BS2 BS4 BS3 BS1 BP2 BP3 BP1 BP4 BP5 BP7 PS2 PS3 PS1 PP1 PP4 PP2 PP3

Evidence Links 3

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.832+G>T variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). The variant is present in <1/100,000 alleles in the gnomAD cohort. (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 23709761, 23124477, 26182300 and SCV000288497.3). In summary, 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, PM2_Supporting, PS4, PM5_Supporting.
Met criteria codes
PM2_Supporting
Not in ExAC or gnomAD.
PM5_Supporting
Apply PM5_Supporting to the variant with the alteration at canonical splicing site.
PVS1_Strong
Variant is in +1 splice site and exon is not in frame.
PS4
Seen in one proband with DGC at 46 whose brother had GC at 54, mother had GC at 50 and MGM had breast cancer at 70 but it is unknown if they also had the variants. Also reported in at least 3 more probands with DGC, at least 2 of whom were <40. Clinical data: Proband: multiple foci early stage gastric cancer on prophylactic gastrectomy (30s). Brother: A/W at 30s (carrier). Mother: gastric cancer at 50s (not tested). Maternal aunt: gastric cancer at 40s (not tested). Clinical data: Single site positivie test in 30 yo. Mother was dx with DGC at 47 and is positive for the alteration (we have her genetic testing report). Maternal aunt died of DGC in her 60s and is also reported to be positive for the alteration, but we don’t have a report. Maternal grandmother died of unspecified cancer in her 50’s. Total of 6 families.
Not Met criteria codes
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
BA1
Not in ExAC or gnomAD.
BS2
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
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
Not in ExAC or gnomAD.
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
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
Multiple lines of splicing evidence predict this variant abolishes a splice site.
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
This variant was reported in 1 previously unreported proband with HDGC. PubMed:26182300
Variant is present in 2 probands with DGC at 33 and 17, respectively, one of whom had a personal and/or family history of sporadic DGC <40 in 3 family members. PubMed:23709761
Variant reported in a 17 year old girl with DGC who had a history of cleft lip and cleft palate. PubMed:23124477
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
Multiple lines of splicing evidence predict this variant abolishes a splice site.
Curation History
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