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]

Variant: NM_004360.4(CDH1):c.3G>A (p.Met1Ile)

CA10583399

239906 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d13fa937-98cf-4da0-956f-8d7d5543f0a3
Approved on: 2023-08-29
Published on: 2023-08-29

HGVS expressions

NM_004360.4:c.3G>A
NM_004360.4(CDH1):c.3G>A (p.Met1Ile)
NC_000016.10:g.68737418G>A
CM000678.2:g.68737418G>A
NC_000016.9:g.68771321G>A
CM000678.1:g.68771321G>A
NC_000016.8:g.67328822G>A
NG_008021.1:g.5127G>A
ENST00000261769.10:c.3G>A
ENST00000261769.9:c.3G>A
ENST00000422392.6:c.3G>A
ENST00000566510.5:c.3G>A
ENST00000566612.5:c.3G>A
ENST00000611625.4:c.3G>A
ENST00000612417.4:c.3G>A
ENST00000621016.4:c.3G>A
NM_004360.3:c.3G>A
NM_001317184.1:c.3G>A
NM_001317185.1:c.-1613G>A
NM_001317186.1:c.-1817G>A
NM_004360.5:c.3G>A
NM_001317184.2:c.3G>A
NM_001317185.2:c.-1613G>A
NM_001317186.2:c.-1817G>A
NM_004360.5(CDH1):c.3G>A (p.Met1Ile)
More

Pathogenic

Met criteria codes 4
PP1_Moderate PS4 PM2_Supporting PVS1
Not Met criteria codes 22
BP5 BP7 BP2 BP3 BP1 BP4 PS2 PS3 PS1 PP4 PP2 PP3 PM6 PM3 PM1 PM4 PM5 BA1 BS3 BS4 BS1 BS2

Evidence Links 0

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.3G>A (p.Met1Ile) variant causes a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (18726070, 2317870, 20066110) (PVS1). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant was found to co-segregate with disease in multiple affected family members, with 5 or 6 meioses observed (PP1_Moderate; PMID: 28202063, 26182300). This variant has also been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 26182300, 20719348, clinical lab internal data). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP Variant Interpretation Guidelines Version 3.1 as specified by the CDH1 Variant Curation Expert Panel: PVS1, PM2_Supporting, PP1_Moderate, PS4.
Met criteria codes
PP1_Moderate
One member with diffuse gastric cancer and 2 members with gastric cancer. All with the mutation
PS4
4 families meet HDGC criteria
PM2_Supporting
Absent from all population databases
PVS1
PVS1 applies to initiation codon variants
Not Met criteria codes
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
Splicing impact predictors predict no effect
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
PP4
One member with diffuse gastric cancer and 2 members with gastric cancer. All with the mutation
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
Splicing impact predictors predict no effect
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
Mutation in CDH1 of G>C rather than G>A in a patient with diffuse gastric cancer. Family member also with mutation and lobular breast cancer
BA1
Absent from all population databases
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
Absent from all population databases
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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