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.2398delC (p.Arg800Alafs)

CA281459

156497 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
UUID: a4959b72-3cf7-4e15-96c5-b96fd19dd327

HGVS expressions

NM_004360.4:c.2398delC
NM_004360.4(CDH1):c.2398delC (p.Arg800Alafs)
NC_000016.10:g.68829756del
CM000678.2:g.68829756del
NC_000016.9:g.68863659del
CM000678.1:g.68863659del
NC_000016.8:g.67421160del
NG_008021.1:g.97465del
ENST00000261769.10:c.2398del
ENST00000261769.9:c.2398del
ENST00000422392.6:c.2215del
ENST00000562118.1:n.616del
ENST00000562836.5:n.2469del
ENST00000566510.5:c.*1064del
ENST00000566612.5:c.*638del
ENST00000611625.4:c.2461del
ENST00000612417.4:c.1853+3202del
ENST00000621016.4:c.1866-4447del
NM_004360.3:c.2398del
NM_001317184.1:c.2215del
NM_001317185.1:c.850del
NM_001317186.1:c.433del
NM_004360.4:c.2398del
NM_004360.5:c.2398del
NM_001317184.2:c.2215del
NM_001317185.2:c.850del
NM_001317186.2:c.433del
NM_004360.5(CDH1):c.2398del (p.Arg800fs)

Pathogenic

Met criteria codes 4
PM2_Supporting PP1 PS4 PVS1_Strong
Not Met criteria codes 22
BP2 BP3 BP1 BP4 BP5 BP7 BS2 BS3 BS4 BS1 PP2 PP3 PP4 BA1 PM6 PM3 PM1 PM4 PM5 PS2 PS3 PS1

Evidence Links 2

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.2398delC (p.Arg800Alafs*16) variant is predicted to result in a premature stop codon that leads to a truncated protein. However, it is located within the nonsense mediated decay resistance region upstream of c.2506G>T (p.Glu836*) (PVS1_Strong). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID 17545690). This variant was also found to co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed (PP1; PMID: 17545690). 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): PVS1_Strong, PM2_Supporting, PS4, PP1.
Met criteria codes
PM2_Supporting
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
3 families meet HDGC criteria (>2 gastric cancer cases; >1 diffuse gastric cancer). 1 additional family with 3 gastric cancer cases (not confirmed DGC), age of diagnosis 35-75 years. Cumulative risk by age 75 years in carriers for gastric cancer was 40% for males and 63% for females, and for breast cancer was 52% for females. All 4 families found to share common haplotype, suggesting a founder effect; and originate from the southeast coast of Newfoundland.

PS4
Kaurah et al., PMID 17545690. 3 families meet HDGC criteria (>2 gastric cancer cases; >1 diffuse gastric cancer). 1 additional family with 3 gastric cancer cases (not confirmed DGC), age of diagnosis 35-75 years. Cumulative risk by age 75 years in carriers for gastric cancer was 40% for males and 63% for females, and for breast cancer was 52% for females. All 4 families found to share common haplotype, suggesting a founder effect; and originate from the southeast coast of Newfoundland. Plus internal lab data.

PVS1_Strong
p.Arg800AlafsTer16. c.2398delC is located in the penultimate exon 15 of ENST00000261769.9 (NM_004360.4); penultimate exon 14 of ENST00000422392.6 (NM_001317184, NM_001317185, NM_001317186); and penultimate exon 16 of ENST00000611625.4. However this exon is not present in the alternatively spliced protein coding transcripts ENST00000621016.4 and ENST00000612417.4 which encode 647aa proteins. However, the premature stop codon (PTC) p.Arg800AlafsTer16 is in the final exon and not downregulated by NMD. Karam et al., 2008 PMID: 18427545 performed allele-specific expression analysis shows that the c.2398delC allele is not expressed at lower levels than the wild-type allele, suggesting c.2398delC transcripts are not downregulated by NMD The p.Arg800Alafs frameshift does alter a substantial portion of the Catenin binding domain (aa787-881) [possible PVS1_STRONG??], but is overall not a substatial proportion of the protein (<10% of 882aa) [PVS1_Moderate]

Not Met criteria codes
BP2
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
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
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
BS2
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
BS4
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
Kaurah et al., PMID 17545690. 3 families meet HDGC criteria (>2 gastric cancer cases; >1 diffuse gastric cancer). 1 additional family with 3 gastric cancer cases (not confirmed DGC), age of diagnosis 35-75 years. Cumulative risk by age 75 years in carriers for gastric cancer was 40% for males and 63% for females, and for breast cancer was 52% for females. All 4 families found to share common haplotype, suggesting a founder effect; and originate from the southeast coast of Newfoundland. Plus internal lab data.

BA1
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
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
PM4
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
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
Approved on: 2023-08-29
Published on: 2023-08-29
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