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_004360.4(CDH1):c.2494G>A (p.Val832Met)

CA157969

12246 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: fa3b9647-d4d2-4091-8d83-e4e2f0f16391
Approved on: 2023-08-10
Published on: 2023-08-10

HGVS expressions

NM_004360.4:c.2494G>A
NM_004360.4(CDH1):c.2494G>A (p.Val832Met)
NC_000016.10:g.68833344G>A
CM000678.2:g.68833344G>A
NC_000016.9:g.68867247G>A
CM000678.1:g.68867247G>A
NC_000016.8:g.67424748G>A
NG_008021.1:g.101053G>A
ENST00000261769.10:c.2494G>A
ENST00000261769.9:c.2494G>A
ENST00000422392.6:c.2311G>A
ENST00000562118.1:n.712G>A
ENST00000562836.5:n.2565G>A
ENST00000566510.5:c.*1160G>A
ENST00000566612.5:c.*734G>A
ENST00000611625.4:c.2557G>A
ENST00000612417.4:c.1854-847G>A
ENST00000621016.4:c.1866-859G>A
NM_004360.3:c.2494G>A
NM_001317184.1:c.2311G>A
NM_001317185.1:c.946G>A
NM_001317186.1:c.529G>A
NM_004360.5:c.2494G>A
NM_001317184.2:c.2311G>A
NM_001317185.2:c.946G>A
NM_001317186.2:c.529G>A
NM_004360.5(CDH1):c.2494G>A (p.Val832Met)

Benign

Met criteria codes 2
BS2 BS1
Not Met criteria codes 24
PS2 PS4 PS1 PS3 PP1 PP4 PP2 PP3 PM3 PM1 PM4 PM5 PM6 PM2 BA1 PVS1 BS3 BS4 BP2 BP3 BP1 BP4 BP7 BP5

Evidence Links 6

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.2494G>A (p.Val832Met) variant has an allele frequency of 0.00175 (0.175%, 33/18,868 alleles) in the East Asian subpopulation of the gnomAD cohort (BS1). This variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS1, BS2.
Met criteria codes
BS2
Observed in 144 patients w/o dx HDGC
BS1
East Asian population from ExAC has an allele frequency of 0.25% (22 alleles) but it is not 99.99% Cl it is a 95% Cl with the lower limit being 0.16%
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
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
Multiple experimental investigations revealed the variant causes reduced cell adhesion and increased cell motility and invasion
Examined the V832M variant and determined that in endothelial cells derived from a cervical carcinoma the variant had no effect on cell motility or cell adhesion PubMed:17668349
Showed that the V832M variant had function 0.67 times that of the wild type PubMed:22850631
Showed an exact mechanism of how V832M would destabilize cell adhesion PubMed:19017792
Showed that the missense mutation causes impaired E-cadherin function and increased cell invasion PubMed:12944922
PP1
Proband with diffuse gastric cancer and the variant and two siblings with gastric cancer and the variant
Proband with diffuse gastric cancer and two siblings with gastric cancer and tested positive for the variant PubMed:12216071
PP4
Multiple families with the variant and either lobular breast cancer or diffuse gastric cancer
Patient with lobular breast cancer at 43 and the variant. Sister had a ductal breast cancer and maternal aunt had an unspecified breast cancer PubMed:20921021
Proband with diffuse gastric cancer and 4 siblings, mother and nephew with gastric cancer PubMed:12216071
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
Splicing predictors show no effect
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
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
East Asian population from ExAC has an allele frequency of 0.25% (22 alleles) but it is not 99.99% Cl it is a 95% Cl with the lower limit being 0.16%
BA1
East Asian population from ExAC has an allele frequency of 0.25% (22 alleles) but it is not 99.99% Cl it is a 95% Cl with the lower limit being 0.16%
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
Multiple experimental investigations revealed the variant causes reduced cell adhesion and increased cell motility and invasion
Examined the V832M variant and determined that in endothelial cells derived from a cervical carcinoma the variant had no effect on cell motility or cell adhesion PubMed:17668349
Showed that the V832M variant had function 0.67 times that of the wild type PubMed:22850631
Showed an exact mechanism of how V832M would destabilize cell adhesion PubMed:19017792
Showed that the missense mutation causes impaired E-cadherin function and increased cell invasion PubMed:12944922
BS4
Proband with diffuse gastric cancer and two siblings with gastric cancer and tested positive for the variant PubMed:12216071
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
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
Splicing predictors show no effect
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
Observed in two individuals with pathogenic variants in other cancer assoc. genes (BRCA2 and MLH1); one has an overlapping phenotype
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