Evidence Repository - Clinical Genome Resources

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.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)

Pathogenic

PS4 PS3 PM2_Supporting

BP5 BP7 BP3 BP2 BP1 BP4 PS2 PS1 PP4 PP1 PP2 PP3 PM4 PM3 PM1 PM5 PM6 PVS1 BA1 BS4 BS3 BS1 BS2

Evidence Links 3

Expert Panel

CDH1 VCEP

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.

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

PM2_Supporting

Absent from population databases

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

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

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

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

BA1

Absent from population databases

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

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