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

CA10577547

234554 (ClinVar)

Gene: CDH1

Condition: hereditary diffuse gastric cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 89320d2b-848b-4794-bcc3-84d990e99660

Approved on: 2018-11-21

Published on: 2020-06-03

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

Pathogenic

• Met criteria codes: PP3 PM2 PP1_Strong PS3 PS4

• Not Met criteria codes: PP2 PP4 PVS1 PM6 BA1 PM1 PM3 PM5 PM4 BS2 BS1 BS4 BS3 BP5 BP7 BP4 BP3 BP1 BP2 PS1 PS2

Expert Panel

Criteria Specification Information

Evidence submitted by expert panel

CDH1 VCEP

The c.1679C>G (p.Thr560Arg) variant is absent in the gnomAD cohort (PM2;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: PM2, PP3, PS3, PP1_Strong, PS4.

Met criteria codes

• 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.
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1_Strong: Total of 8 segregations across 4 families
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: Four published families plus internal lab data (SCV000580704.2)

Not Met criteria codes

• PP2: 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
• PVS1: 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
• BA1: 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
• PM3: 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
• PM4: 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
• BS1: 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
• 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: 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.
• BP3: 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
• BP2: 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
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline