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.2195G>A (p.Arg732Gln)

CA16615410

406663 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 0b968ecb-5432-4588-a812-7dd328f2b93d
Approved on: 2023-11-27
Published on: 2023-12-22

HGVS expressions

NM_004360.4:c.2195G>A
NM_004360.4(CDH1):c.2195G>A (p.Arg732Gln)
NC_000016.10:g.68828204G>A
CM000678.2:g.68828204G>A
NC_000016.9:g.68862107G>A
CM000678.1:g.68862107G>A
NC_000016.8:g.67419608G>A
NG_008021.1:g.95913G>A
ENST00000261769.10:c.2195G>A
ENST00000261769.9:c.2195G>A
ENST00000422392.6:c.2012G>A
ENST00000562118.1:n.413G>A
ENST00000562836.5:n.2266G>A
ENST00000566510.5:c.*861G>A
ENST00000566612.5:c.*435G>A
ENST00000611625.4:c.2258G>A
ENST00000612417.4:c.1853+1650G>A
ENST00000621016.4:c.1866-5999G>A
NM_004360.3:c.2195G>A
NM_001317184.1:c.2012G>A
NM_001317185.1:c.647G>A
NM_001317186.1:c.230G>A
NM_004360.5:c.2195G>A
NM_001317184.2:c.2012G>A
NM_001317185.2:c.647G>A
NM_001317186.2:c.230G>A
NM_004360.5(CDH1):c.2195G>A (p.Arg732Gln)
More

Pathogenic

Met criteria codes 3
PM2_Supporting PS4 PS3
Not Met criteria codes 23
BS4 BS3 BS1 BS2 BP5 BP7 BP3 BP2 BP1 BP4 PS2 PS1 BA1 PP4 PP1 PP2 PP3 PM6 PVS1 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.2195G>A variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is an RNA assay demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 17545690 15235021). This variant has also been reported in at least 12 families with HDGC criteria (PS4; PMID: 17545690 15235021 and laboratory internal data). 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, PS3, PS4.
Met criteria codes
PM2_Supporting
Absent from population databases
PS4
At least 12 families are known to meet HDGC criteria.
Variant identified in family meeting the following criteria: two or more documented cases of DGC in first degree relatives, with at least one diagnosed before age 50 PubMed:15235021
Variant identified in family with strong family history of GC, DGC, BC and LBC PubMed:17545690
PS3
An RNA assay demonstrates the creation of abnormal out-of-frame transcript (RNA data: r.2165_2196del32p.I722KFS*15; laboratory internal data)
Functional in vitro assays suggest that the variant affects cell-cell adhesion and cell invasion. PubMed:15235021
RT-PCR analysis demonstrated that the variant results in complex splicing and deletion of 32 base pairs at the start of exon 14. PubMed:17545690
Not Met criteria codes
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
In-frame splicing variant with in vitro functional studies
BS1
Absent from population databases
BS2
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
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
In silico analysis using the software NNSPLICE and NetGene2 predicted that the variant creates a new acceptor splice site. PubMed:17545690
BP4
Variant creates a new splice acceptor site.
In silico analysis using the software NNSPLICE and NetGene2 predicted that the variant creates a new acceptor splice site. PubMed:17545690
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
A variant in the same codon and of uncertain significance (p.R732W) was identified in an individual with neuroblastoma. PubMed:26580448
BA1
Absent from population databases
PP4
Variant identified in family meeting the following criteria: two or more documented cases of DGC in first degree relatives, with at least one diagnosed before age 50 PubMed:15235021
Variant identified in family with strong family history of GC, DGC, BC and LBC PubMed:17545690
PP1
Variant identified in proband's brother with GC dx at 65, but does not meet PP1_supporting (3-4 meioses)
PP2
In silico analysis using the software NNSPLICE and NetGene2 predicted that the variant creates a new acceptor splice site. PubMed:17545690
PP3
PS3 has been applied for the experimental data (RNA assay).
In silico analysis using the software NNSPLICE and NetGene2 predicted that the variant creates a new acceptor splice site. PubMed:17545690
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
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
A variant in the same codon and of uncertain significance (p.R732W) was identified in an individual with neuroblastoma. PubMed:26580448
Curation History
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