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.371G>A (p.Arg124His)

CA294161

141538 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 9223aee2-5569-48ce-95d5-b9bc870156ea
Approved on: 2023-08-10
Published on: 2023-08-10

HGVS expressions

NM_004360.5:c.371G>A
NM_004360.5(CDH1):c.371G>A (p.Arg124His)
NC_000016.10:g.68801877G>A
CM000678.2:g.68801877G>A
NC_000016.9:g.68835780G>A
CM000678.1:g.68835780G>A
NC_000016.8:g.67393281G>A
NG_008021.1:g.69586G>A
ENST00000261769.10:c.371G>A
ENST00000261769.9:c.371G>A
ENST00000422392.6:c.371G>A
ENST00000561751.1:n.138G>A
ENST00000562836.5:n.442G>A
ENST00000564676.5:n.653G>A
ENST00000564745.1:n.366G>A
ENST00000566510.5:c.371G>A
ENST00000566612.5:c.371G>A
ENST00000611625.4:c.371G>A
ENST00000612417.4:c.371G>A
ENST00000621016.4:c.371G>A
NM_004360.3:c.371G>A
NM_001317184.1:c.371G>A
NM_001317185.1:c.-1245G>A
NM_001317186.1:c.-1449G>A
NM_004360.4:c.371G>A
NM_001317184.2:c.371G>A
NM_001317185.2:c.-1245G>A
NM_001317186.2:c.-1449G>A
More

Likely Benign

Met criteria codes 1
BS2
Not Met criteria codes 25
BP7 BP5 BP3 BP4 BP1 BP2 PVS1 PS1 PS2 PS3 PS4 PP3 PP2 PP4 PP1 PM6 PM2 PM5 PM4 PM3 PM1 BA1 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.371G>A (p.Arg124His) missense variant has a frequency of 0.02010% in Africans (5/24870 alleles) in the gnomAD v2.1.1 cohort. This variant has been observed in ≥10 (31) individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000637819.6, SCV000184938.6). 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): BS2.
Met criteria codes
BS2
Observed in 31 individuals without HDGC phenotypes (SCV000637819.6, SCV000184938.6).
Not Met criteria codes
BP7
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
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
VarSEAK: Class 1, No splicing effect. SpliceAI: No splicing predictions. SSF - no change. MaxEnt = 8.87 ⇒ 8.35 (-5.9%) NNSplice= 0.89 ⇒ 0.91 (+1.4%)
BP1
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
PVS1
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No functional studies.
PS4
PMID: 24493355 - DGC at 39 years old (<40 or 50 years old). PS4 cannot be applied to variants in which less than 30% of reported individuals meet HDGC criteria.
PP3
VarSEAK: Class 1, No splicing effect. SpliceAI: No splicing predictions.
PP2
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
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
gnomAD 2.1.1 = 5/24870 alleles in Africans (0.02010%). gnomAD 3.1 = 4/152104 alleles total (0.002630%) > 0.002%.
PM5
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
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
BA1
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 functional studies.
BS1
MAF <0.1% gnomAD 2.1.1 = 5/24870 alleles in Africans (0.02010%). gnomAD 3.1 = 4/152104 alleles total (0.002630%).
Curation History
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