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

Variant: NM_004360.4(CDH1):c.1003C>T (p.Arg335Ter)

CA166866

136055 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: ce612d02-2bbe-433b-a871-e4ddcfeca78d

HGVS expressions

NM_004360.4:c.1003C>T
NM_004360.4(CDH1):c.1003C>T (p.Arg335Ter)
NC_000016.10:g.68811854C>T
CM000678.2:g.68811854C>T
NC_000016.9:g.68845757C>T
CM000678.1:g.68845757C>T
NC_000016.8:g.67403258C>T
NG_008021.1:g.79563C>T
ENST00000261769.10:c.1003C>T
ENST00000261769.9:c.1003C>T
ENST00000422392.6:c.1003C>T
ENST00000561751.1:n.625C>T
ENST00000562836.5:n.1074C>T
ENST00000566510.5:c.847C>T
ENST00000566612.5:c.1003C>T
ENST00000611625.4:c.1003C>T
ENST00000612417.4:c.1003C>T
ENST00000621016.4:c.1003C>T
NM_004360.3:c.1003C>T
NM_001317184.1:c.1003C>T
NM_001317185.1:c.-613C>T
NM_001317186.1:c.-817C>T
NM_004360.5:c.1003C>T
NM_001317184.2:c.1003C>T
NM_001317185.2:c.-613C>T
NM_001317186.2:c.-817C>T
NM_004360.5(CDH1):c.1003C>T (p.Arg335Ter)

Pathogenic

Met criteria codes 3
PP1_Strong PVS1 PM5_Supporting
Not Met criteria codes 23
BS2 BS3 BS4 BS1 BP2 BP3 BP1 BP4 BP5 BP7 PS2 PS4 PS3 PS1 PP4 PP2 PP3 BA1 PM6 PM2 PM3 PM1 PM4

Evidence Links 3

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.1003C>T (p.Arg335*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant was found to co-segregate with disease in multiple affected family members, with >7 meioses observed across at least two families (PP1_Strong; PMID: 16061854, 22723466, 17522512). 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, PP1_Strong, PM5_Supporting.
Met criteria codes
PP1_Strong
Variant seen in >4 families where it segregated with HDGC or LBC in >20 relatives.
Proband with HDGC and Arg335X variant. Both his children and his brother and sister were all carriers and had HDGC. The proband's nephew was the only one tested who was a carrier but unaffected at the time of publication. 5 affected carriers altogether. PubMed:22723466
The Arg335X variant segregated with disease in at least 11 people from one family, with 3 others being unaffected carriers. PubMed:17522512
This variant was found in one proband with DGC who had 8 relatives with GC, 2 of which were confirmed DGC. PubMed:16061854
PVS1
Nonsense variant in exon 7/16
PM5_Supporting
Apply PM5_Supporting to nonsense/frameshift variants that are predicted/proved to undergo NMD.
Not Met criteria codes
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
Proband with HDGC and Arg335X variant. Both his children and his brother and sister were all carriers and had HDGC. The proband's nephew was the only one tested who was a carrier but unaffected at the time of publication. 5 affected carriers altogether. PubMed:22723466
The Arg335X variant segregated with disease in at least 11 people from one family, with 3 others being unaffected carriers. PubMed:17522512
This variant was found in one proband with DGC who had 8 relatives with GC, 2 of which were confirmed DGC. PubMed:16061854
BS1
0.003% in GnomAD - 1 South Asian allele.
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
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
PP4
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
BA1
0.003% in GnomAD - 1 South Asian allele.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
0.003% in GnomAD - 1 South Asian allele.
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
Approved on: 2023-08-29
Published on: 2023-08-29
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