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]
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Variant: NM_004360.5(CDH1):c.223T>C (p.Phe75Leu)

CA167218

142040 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 3c3d6283-80a7-4274-840e-3b4a5ee56708

HGVS expressions

NM_004360.5:c.223T>C
NM_004360.5(CDH1):c.223T>C (p.Phe75Leu)
NC_000016.10:g.68801729T>C
CM000678.2:g.68801729T>C
NC_000016.9:g.68835632T>C
CM000678.1:g.68835632T>C
NC_000016.8:g.67393133T>C
NG_008021.1:g.69438T>C
ENST00000261769.10:c.223T>C
ENST00000261769.9:c.223T>C
ENST00000422392.6:c.223T>C
ENST00000562836.5:n.294T>C
ENST00000564676.5:n.505T>C
ENST00000564745.1:n.218T>C
ENST00000566510.5:c.223T>C
ENST00000566612.5:c.223T>C
ENST00000611625.4:c.223T>C
ENST00000612417.4:c.223T>C
ENST00000621016.4:c.223T>C
NM_004360.3:c.223T>C
NM_001317184.1:c.223T>C
NM_001317185.1:c.-1393T>C
NM_001317186.1:c.-1597T>C
NM_004360.4:c.223T>C
NM_001317184.2:c.223T>C
NM_001317185.2:c.-1393T>C
NM_001317186.2:c.-1597T>C

Likely Benign

Met criteria codes 2
BS2 PM2_Supporting
Not Met criteria codes 24
PS2 PS4 PS3 PS1 BP5 BP7 BP2 BP3 BP4 BP1 PP4 PP1 PP3 PP2 BA1 PM6 PVS1 PM3 PM1 PM4 PM5 BS4 BS3 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
CDH1 VCEP
The c.223T>C (p.Phe75Leu) missense variant has a frequency of 0.000003977 (1 of 251,418) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.000008795 (1 of 113,700) in the Non-Finnish European population (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been observed in ≥10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2). In summary, the clinical significance of this variant is classified as of likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_supporting, BS2.
Met criteria codes
BS2
12 probands without personal or family history of DGC or LBC. 7 of the 12 have a personal history of breast cancer (IDC or NOS).
PM2_Supporting
variant present in 1 allele in gnomAD v2.1.1 (1 of 113,700 in NFE)
Not Met criteria codes
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
NM_004360.5(CDH1):c.225C>G (p.Phe75Leu) is VUS by Expert Panel
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
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
BA1
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
PVS1
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
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
Approved on: 2023-08-18
Published on: 2023-08-18
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