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]
Link to SEPIO compliant JSON-LD document

Variant: NM_004360.4(CDH1):c.1679C>G (p.Thr560Arg)

CA10577547

234554 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 89320d2b-848b-4794-bcc3-84d990e99660

HGVS expressions

NM_004360.4:c.1679C>G
NM_004360.4(CDH1):c.1679C>G (p.Thr560Arg)
NC_000016.10:g.68819393C>G
CM000678.2:g.68819393C>G
NC_000016.9:g.68853296C>G
CM000678.1:g.68853296C>G
NC_000016.8:g.67410797C>G
NG_008021.1:g.87102C>G
ENST00000261769.10:c.1679C>G
ENST00000261769.9:c.1679C>G
ENST00000422392.6:c.1496C>G
ENST00000562836.5:n.1750C>G
ENST00000566510.5:c.*345C>G
ENST00000566612.5:c.1566-2608C>G
ENST00000611625.4:c.1742C>G
ENST00000612417.4:c.1679C>G
ENST00000621016.4:c.1679C>G
NM_004360.3:c.1679C>G
NM_001317184.1:c.1496C>G
NM_001317185.1:c.131C>G
NM_001317186.1:c.-254-2608C>G
NM_004360.5:c.1679C>G
NM_001317184.2:c.1496C>G
NM_001317185.2:c.131C>G
NM_001317186.2:c.-254-2608C>G
NM_004360.5(CDH1):c.1679C>G (p.Thr560Arg)

Pathogenic

Met criteria codes 5
PP1_Strong PS4 PS3 PM2_Supporting PP3
Not Met criteria codes 21
BA1 BS2 BS3 BS4 BS1 BP3 BP2 BP1 BP4 PVS1 BP5 BP7 PS2 PS1 PP4 PP2 PM6 PM4 PM3 PM1 PM5

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.1679C>G (p.Thr560Arg) variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There are at least 3 in silico predictors in agreement that this variant affects splicing (PP3). There is also an RNA assay demonstrating abnormal out-of-frame transcript (PS3; PMID: 27880784). Additionally, the variant was found to co-segregation with disease in multiple affected family members, with >7 meioses observed across at least 4 families (PP1_Strong; PMID: 27880784, 29769627). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 27880784, 29769627, 23709761 and SCV000580704.2). 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): PM2_Supporting, PP3, PS3, PP1_Strong, PS4.
Met criteria codes
PP1_Strong
Total of 8 segregations across 4 families
Six segregations across 3 families PubMed:29769627
PS4
Four published families plus internal lab data (SCV000580704.2)
Shows multiple family members with the CDH1 mutation and all 3 have gastric cancer PubMed:27880784
Reports segregation in three unrelated Spanish families PubMed:29769627
Proband with diffuse gastric cancer at age 27 PubMed:23709761
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2_Supporting
Absent from controls in gnomAD
PP3
Predicted splicing variant. Splicing analysis shows the potential altering of splices sites through the activation of new cryptic donor and acceptor sites and the creation of an ESS site.
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
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
Six segregations across 3 families PubMed:29769627
BS1
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
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
Predicted splicing variant. Splicing analysis shows the potential altering of splices sites through the activation of new cryptic donor and acceptor sites and the creation of an ESS site.
PVS1
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
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
Shows multiple family members with the CDH1 mutation and all 3 have gastric cancer
PP2
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
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
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2023-08-29
Published on: 2023-08-29
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