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]

Variant: NM_004360.4(CDH1):c.2195G>A (p.Arg732Gln)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA16615410

406663 (ClinVar)

Gene: CDH1

Condition: hereditary diffuse gastric cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0b968ecb-5432-4588-a812-7dd328f2b93d

Approved on: 2018-11-21

Published on: 2020-06-03

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

Likely Pathogenic

PS3 PS4_Moderate PP3 PM2

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

Evidence Links 3

Expert Panel

CDH1 VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

CDH1 VCEP

The c.2195G>A (p.Arg732Gln) variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). This variant is predicted to affect splicing by at least 3 in silico splicing predictors in agreement (PP3). Additionally, 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 2 families meeting HDGC clinical criteria (PS4_Moderate; PMID: 17545690 15235021). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PM2, PP3, PS3, PS4_Moderate.

PS3

In-frame splicing variant with in vitro functional studies

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

Functional in vitro assays suggest that the variant affects cell-cell adhesion and cell invasion. PubMed:15235021

PS4_Moderate

Proband meets IGCLC criteria with strong family history; 2 additional HDGC families reported in the literature

Variant identified in family with strong family history of GC, DGC, BC and LBC PubMed:17545690

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

PP3

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

PM2

Absent from population databases

PS1

A variant in the same codon and of uncertain significance (p.R732W) was identified in an individual with neuroblastoma. PubMed:26580448

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

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

PP4

Variant identified in family with strong family history of GC, DGC, BC and LBC PubMed:17545690

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

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

PM5

A variant in the same codon and of uncertain significance (p.R732W) was identified in an individual with neuroblastoma. PubMed:26580448

PM4

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

PVS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BA1

Absent from population databases

BS1

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

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

BP4

Variant creates a new splice acceptor site.

BP3

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

BP2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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