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]

Variant: NM_004360.5(CDH1):c.48+1G>A

CA396451431

449341 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8608d63b-7b00-4c76-a9f7-a0b9a5502446
Approved on: 2023-08-29
Published on: 2023-08-29

HGVS expressions

NM_004360.5:c.48+1G>A
NM_004360.5(CDH1):c.48+1G>A
NC_000016.10:g.68737464G>A
CM000678.2:g.68737464G>A
NC_000016.9:g.68771367G>A
CM000678.1:g.68771367G>A
NC_000016.8:g.67328868G>A
NG_008021.1:g.5173G>A
ENST00000261769.10:c.48+1G>A
ENST00000261769.9:c.48+1G>A
ENST00000422392.6:c.48+1G>A
ENST00000566510.5:c.48+1G>A
ENST00000566612.5:c.48+1G>A
ENST00000611625.4:c.48+1G>A
ENST00000612417.4:c.48+1G>A
ENST00000621016.4:c.48+1G>A
NM_004360.3:c.48+1G>A
NM_001317184.1:c.48+1G>A
NM_001317185.1:c.-1568+1G>A
NM_001317186.1:c.-1772+1G>A
NM_004360.4:c.48+1G>A
NM_001317184.2:c.48+1G>A
NM_001317185.2:c.-1568+1G>A
NM_001317186.2:c.-1772+1G>A
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Pathogenic

Met criteria codes 5
PM2_Supporting PM5_Supporting PS4_Moderate PP1_Moderate PVS1_Strong
Not Met criteria codes 21
BA1 PM4 PM3 PM1 PM6 BS2 BS3 BS4 BS1 BP3 BP2 BP1 BP4 BP7 BP5 PS2 PS1 PS3 PP4 PP2 PP3

Evidence Links 2

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.48+1G>A 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). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 20719348, 24366306). The variant was also found to co-segregate with disease in multiple affected family members, with 5 or 6 meioses observed (PP1_Moderate; SCV000617359.1). 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_Moderate and PP1_Moderate, PM5_Supporting.
Met criteria codes
PM2_Supporting
Absent from control databases.
PM5_Supporting
Apply PM5_Supporting to the variant with the alteration at canonical splicing site.
PS4_Moderate
Proband with DGC and age of dx of 74, and two first-degree relatives with GC (one diffuse and one unknown type). Reported in a patient with signet cell carcinoma of the cecum and a family history of diffuse gastric cancer. (PMID: 20719348). Additionally reported in an individual with bilateral LCIS and ILC, age of dx of 51 and family history of breast cancer (no family history of gastric cancer) (PMID: 24366306).
Identified in a patient with signet cell carcinoma of the cecum and family history of diffuse gastric cancer. PubMed:20719348
Identified in an individual with bilateral LCIS and ILC, age of dx of 51 and family history of breast cancer. PubMed:24366306
PP1_Moderate
Clinical data from GeneDx: Available clinical information for those who are POSITIVE: 4 individuals: signet foci on prophylactic gastrectomy (2 in their 40s and 2 in their 20s) 1 individual: DGC (dx 40s) 1 individual: colon cancer with signet ring cell features (dx 70s) Available clinical information for those with unknown genetic status unknown: 3 individuals: stomach cancer (1 in their 60s and 2 in their 40s) 1 individual: colon cancer (dx 80s)
PVS1_Strong
Variant at canonical +/- 1 or 2 splice sites
Not Met criteria codes
BA1
Absent from control databases.
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
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
Absent from control databases.
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
BP1
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
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
PS2
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
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
Proband with DGC and age of dx of 74, and two first-degree relatives with GC (one diffuse and one unknown type). Reported in a patient with signet cell carcinoma of the cecum and a family history of diffuse gastric cancer. Additionally reported in an individual with bilateral LCIS and ILC, age of dx of 51 and family history of breast cancer (no family history of gastric cancer).
Identified in a patient with signet cell carcinoma of the cecum and family history of diffuse gastric cancer. PubMed:20719348
Identified in an individual with bilateral LCIS and ILC, age of dx of 51 and family history of breast cancer. PubMed:24366306
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
Curation History
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