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.8C>G (p.Pro3Arg)

CA294410

142469 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: e8086e46-6b34-49be-97a3-19ddcfa1b1db
Approved on: 2023-08-17
Published on: 2023-08-17

HGVS expressions

NM_004360.4:c.8C>G
NM_004360.4(CDH1):c.8C>G (p.Pro3Arg)
NC_000016.10:g.68737423C>G
CM000678.2:g.68737423C>G
NC_000016.9:g.68771326C>G
CM000678.1:g.68771326C>G
NC_000016.8:g.67328827C>G
NG_008021.1:g.5132C>G
ENST00000261769.10:c.8C>G
ENST00000261769.9:c.8C>G
ENST00000422392.6:c.8C>G
ENST00000566510.5:c.8C>G
ENST00000566612.5:c.8C>G
ENST00000611625.4:c.8C>G
ENST00000612417.4:c.8C>G
ENST00000621016.4:c.8C>G
NM_004360.3:c.8C>G
NM_001317184.1:c.8C>G
NM_001317185.1:c.-1608C>G
NM_001317186.1:c.-1812C>G
NM_004360.5:c.8C>G
NM_001317184.2:c.8C>G
NM_001317185.2:c.-1608C>G
NM_001317186.2:c.-1812C>G
NM_004360.5(CDH1):c.8C>G (p.Pro3Arg)

Likely Benign

Met criteria codes 1
BS2
Not Met criteria codes 25
PVS1 BP5 BP7 BP2 BP3 BP4 BP1 BA1 PS2 PS1 PS4 PS3 PP4 PP1 PP3 PP2 PM6 PM2 PM3 PM1 PM4 PM5 BS4 BS3 BS1

Evidence Links 1

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.8C>G (p.Pro3Arg) variant has an allele frequency of 0.00025 (39/155276) in gnomAD and is observed in multiple subpopulations, with a maximum frequency of 0.00072 (7/9712) in the European (Finnish) subpopulation (http://gnomad.broadinstitute.org). This variant was observed more than 70 probands without a personal history of DGC, SRC tumours or LBC and whose families do not meet HDGC clinical criteria (BS2; SCV000210891.12, SCV000186617.6). The variant has also been identified in at least 5 individuals with LBC but whose families do not meet HDGC clinical criteria (PMID: 20921021, SCV000210891.12). This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. However, localization to the plasma membrane was not affected when the variant was expressed in cells lacking endogenous expression of E-cadherin (PMID: 20921021). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
Met criteria codes
BS2
This variant has been observed in 22 probands without a personal history of DGC, SRC tumours or LBC and whose families do not meet HDGC clinical criteria (SCV000210891.12). The variant has been observed in an additional 63 individuals, 51 of whom have clinical data available (SCV000186617.6).
Not Met criteria codes
PVS1
Not applicable.
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
Not applicable.
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
Not applicable.
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
Not applicable.
BA1
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
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
This variant was identified in an individual with LBC at 38 years and family history of breast cancer (PMID: 20921021). This variant has also been identified in four individuals with LBC but whose families did not meet HDGC clinical criteria.
This variant was identified in an individual with lobular breast cancer at 38 years and family history of breast cancer. PubMed:20921021
PS3
This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. Localization to the plasma membrane was not affected when this variant was expressed in cells lacking endogenous expression E-cadherin. PubMed:20921021
PP4
Not applicable.
PP1
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
PP2
Not applicable.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
Not applicable.
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
Not applicable.
PM5
Not applicable.
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. Localization to the plasma membrane was not affected when this variant was expressed in cells lacking endogenous expression E-cadherin (PMID: 20921021).
This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. Localization to the plasma membrane was not affected when this variant was expressed in cells lacking endogenous expression E-cadherin. PubMed:20921021
BS1
This variant has an allele frequency of 0.00025 (39/155276) in gnomAD and 0.00009 in ExAC (1/10836). In gnomAD, the allele is observed in multiple subpopulations and has a maximum frequency of 0.00072 (7/9712) in the European (Finnish) subpopulation.
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