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.2343A>T (p.Glu781Asp)

CA151521

127923 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: a111a578-1fc8-4793-9f23-269d537cd6a8

HGVS expressions

NM_004360.4:c.2343A>T
NM_004360.4(CDH1):c.2343A>T (p.Glu781Asp)
NC_000016.10:g.68829701A>T
CM000678.2:g.68829701A>T
NC_000016.9:g.68863604A>T
CM000678.1:g.68863604A>T
NC_000016.8:g.67421105A>T
NG_008021.1:g.97410A>T
ENST00000261769.10:c.2343A>T
ENST00000261769.9:c.2343A>T
ENST00000422392.6:c.2160A>T
ENST00000562118.1:n.561A>T
ENST00000562836.5:n.2414A>T
ENST00000566510.5:c.*1009A>T
ENST00000566612.5:c.*583A>T
ENST00000611625.4:c.2406A>T
ENST00000612417.4:c.1853+3147A>T
ENST00000621016.4:c.1866-4502A>T
NM_004360.3:c.2343A>T
NM_001317184.1:c.2160A>T
NM_001317185.1:c.795A>T
NM_001317186.1:c.378A>T
NM_004360.5:c.2343A>T
NM_001317184.2:c.2160A>T
NM_001317185.2:c.795A>T
NM_001317186.2:c.378A>T
NM_004360.5(CDH1):c.2343A>T (p.Glu781Asp)

Likely Benign

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

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.2343A>T (p.Glu781Asp) missense variant has a frequency of 0.00001 (4 of 282,860) in gnomAD, with a maximum allele frequency of 0.00004 (1 of 24,970) in the African subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in ≥100 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000149761.14, SCV000185618.5, SCV000288464.7). Although functional impact of this variant was reported from in vitro assays, functional assays except splicing assay are not applicable to CDH1 according to the CDH1 specific variant interpretation criteria. 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
Observed in over 100 patients do not show HDGC phenotype combined at Invitae, Ambry and GeneDx.
Not Met criteria codes
PVS1
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
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
BP4
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
BS4
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
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
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
PM2
Variant present in 4 individuals in gnomAD. 1 of 24970 alleles in the African population. 3 of 129176 alleles in the NFE population (> 1 in 50,000 alleles)
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
To our knowledge, this variant has not been observed in a family meeting HDGC criteria. The variant has been observed in several individuals with ILC, however data from GeneDx indicates that 1/20 (5.2%) of all probands with a personal history of breast cancer and known histology that are undergoing multigene panel testing report ILC. Ambry and GeneDx each report 23 individuals with breast cancer and this variant, and each report one of these cases as ILC. Therefore, 2 out of 46 = 4.3% and corresponds to the GeneDx acquisition numbers noted above.
PS3
Although this variant was reported to result in instability of E-cadherin at the plasma membrane with a possible effect on cell-cell adhesion from in vitro assays, functional assays except splicing assay are not applicable to CDH1 according to the CDH1 specification criteria.
PS1
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
Approved on: 2023-08-17
Published on: 2023-08-17
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