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

Approved on: 2023-08-29

Published on: 2023-08-29

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: PVS1_Strong PM2_Supporting PS4 PP1

• Not Met criteria codes: PM6 PM3 PM1 PM4 PM5 BA1 BS3 BS4 BS1 BS2 BP5 BP7 BP2 BP3 BP1 BP4 PS2 PS3 PS1 PP2 PP3 PP4

Expert Panel

CDH1 VCEP

Criteria Specification Information

Criteria Specification: ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1

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

• 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]
• PM2_Supporting: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• 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.
• 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.

Not Met criteria codes

• 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
• BA1: 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
• BS1: 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
• 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
• 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
• 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
• 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.