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_004360.5(CDH1):c.820G>A (p.Gly274Ser)

CA194486

186326 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: a5aaee48-e09b-460f-91c0-455f0065cfa0

HGVS expressions

NM_004360.5:c.820G>A
NM_004360.5(CDH1):c.820G>A (p.Gly274Ser)
NC_000016.10:g.68810329G>A
CM000678.2:g.68810329G>A
NC_000016.9:g.68844232G>A
CM000678.1:g.68844232G>A
NC_000016.8:g.67401733G>A
NG_008021.1:g.78038G>A
ENST00000261769.10:c.820G>A
ENST00000261769.9:c.820G>A
ENST00000422392.6:c.820G>A
ENST00000561751.1:n.455-1355G>A
ENST00000562836.5:n.891G>A
ENST00000566510.5:c.664G>A
ENST00000566612.5:c.820G>A
ENST00000611625.4:c.820G>A
ENST00000612417.4:c.820G>A
ENST00000621016.4:c.820G>A
NM_004360.3:c.820G>A
NM_001317184.1:c.820G>A
NM_001317185.1:c.-796G>A
NM_001317186.1:c.-1000G>A
NM_004360.4:c.820G>A
NM_001317184.2:c.820G>A
NM_001317185.2:c.-796G>A
NM_001317186.2:c.-1000G>A

Benign

Met criteria codes 3
BP2_Strong BS2 BS1
Not Met criteria codes 23
PM5 PM4 PM3 PM1 PS2 PS4 PS1 PS3 PM6 PM2 BA1 PVS1 BP3 BP4 BP1 BP7 BP5 BS4 BS3 PP1 PP4 PP3 PP2

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.820G>A (p.Gly274Ser) variant has been observed in >10 (25) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000760786.3, SCV000216659.5 and SCV000520889.4). This variant was observed in the homozygous state in an individual without a personal and/or family history of diffuse gastric cancer or lobular breast cancer (BP2_Strong; SCV000520889.4). The c.820G>A variant has an allele frequency of 0.001037 (0.1037%, 5/4822 alleles) in the South Asian subpopulation of the gnomAD v.3.1 cohort (BS1). In summary, the clinical significance of this variant is benign, ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2_Strong, BS1.
Met criteria codes
BP2_Strong
SCV000520889.4 - Observed in the homozygous state in a child <5 yrs old with no reported family history of gastric or breast cancer.
BS2
SCV000760786.3, SCV000216659.5 and SCV000520889.4: >10 (25) individuals w/o DGC, SRC tumors, or LBC & whose families do not suggest HDGC
BS1
gnomAD v2.1.1 = 0.072% in South Asians. gnomAD v3.1 = 5 of 4822 alleles, 0.1037% in South Asians.
Not Met criteria codes
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
PMID: 24204729 and 22543498 - one 62-year-old proband with mixed type gastric cancer (criteria not met). SCV000760786.3 - gastroesophageal junction adenocarcinoma (signet ring cell) in 40s - meets HDGC criteria (<50 years old), but cannot be used if BS1 is met.
PS1
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
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
BA1
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
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
SpliceAI: Donor Loss, score = 0.08 at 0 bp. VarSeak: Class 1, No splicing effect.
BP1
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
BP5
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
PMID: 25388006 and PMID: 22543498 - variant behaves similarly to wildtype protein in terms of level and pattern of expression (high E-cadherin concentration at the plasma membrane and absence of cytoplasmic protein aggregates), cell–cell adhesion competence as well as invasive capacity. PMID: 22543498 - no impact on splicing.
PP1
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
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
Approved on: 2023-08-09
Published on: 2023-08-10
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