The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

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

CA16615410

406663 (ClinVar)

Gene: CDH1
Condition: hereditary diffuse gastric cancer
Inheritance Mode: Autosomal dominant inheritance
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
More

Likely Pathogenic

Met criteria codes 4
PS3 PS4_Moderate PP3 PM2
Not Met criteria codes 22
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

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.
Met criteria codes
PS3
In-frame splicing variant with in vitro functional studies

PS4_Moderate
Proband meets IGCLC criteria with strong family history; 2 additional HDGC families reported in the literature

PP3
Variant creates a new splice acceptor site.

PM2
Absent from population databases
Not Met criteria codes
PS1
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
PP4
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
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
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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