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_004360.4(CDH1):c.1565+1G>T

CA164768

141206 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 86d8c205-2b95-4efe-99b1-05c23e281f1d
Approved on: 2023-08-25
Published on: 2023-08-25

HGVS expressions

NM_004360.4:c.1565+1G>T
NM_004360.4(CDH1):c.1565+1G>T
NC_000016.10:g.68815760G>T
CM000678.2:g.68815760G>T
NC_000016.9:g.68849663G>T
CM000678.1:g.68849663G>T
NC_000016.8:g.67407164G>T
NG_008021.1:g.83469G>T
ENST00000261769.10:c.1565+1G>T
ENST00000261769.9:c.1565+1G>T
ENST00000422392.6:c.1382+1G>T
ENST00000562836.5:n.1636+1G>T
ENST00000566510.5:c.*231+1G>T
ENST00000566612.5:c.1565+1G>T
ENST00000611625.4:c.1628+1G>T
ENST00000612417.4:c.1565+1G>T
ENST00000621016.4:c.1565+1G>T
NM_004360.3:c.1565+1G>T
NM_001317184.1:c.1382+1G>T
NM_001317185.1:c.17+1G>T
NM_001317186.1:c.-255+1G>T
NM_004360.5:c.1565+1G>T
NM_001317184.2:c.1382+1G>T
NM_001317185.2:c.17+1G>T
NM_001317186.2:c.-255+1G>T
NM_004360.5(CDH1):c.1565+1G>T
More

Pathogenic

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

Evidence Links 4

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.1565+1G>T variant 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: 26182300, 11968084). The variant was also found to co-segregate with disease in at least two families, with 6 meioses observed (PP1_Moderate; internal laboratory contributors). 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
PVS1_Strong
Variant in canonical donor splice site of intron 10
PM2_Supporting
Absent in gnomAD
PM5_Supporting
Apply PM5_Supporting to the variant with the alteration at canonical splicing site.
PS4_Moderate
At least two families meeting HDGC clinical criteria (PMID: 26182300, 11968084)
Review article PubMed:20373070
Two confirmed cases of diffuse gastric cancer in sisters aged 56 and 49 years, and a paternal uncle also developed gastric cancer of unknown histology. Family is of Arabic ethnicity. PubMed:11968084
Unaffected caucasian proband, with a family history of three gastric cancers including 1 confirmed DGC PubMed:26182300
PP1_Moderate
2 informative meioses (GeneDx). 4 informative meioses (SCV000184399.5)
Not Met criteria codes
PM6
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
BS2
Colon carcinoma diagnosed at 70 years. State case is a HDGC patient, but gives no evidence of a gastric cancer diagnosis. PubMed:18788075
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
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
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
PS3
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
PP4
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
Curation History
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