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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_004360.4(CDH1):c.2396C>G (p.Pro799Arg)

CA163797

140871 (ClinVar)

Gene: CDH1
Condition: CDH1-related diffuse gastric and lobular breast cancer
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: adcfd805-c238-4e80-b9ad-f6fa541ab04d
Approved on: 2023-08-21
Published on: 2023-08-21

HGVS expressions

NM_004360.4:c.2396C>G
NM_004360.4(CDH1):c.2396C>G (p.Pro799Arg)
NC_000016.10:g.68829754C>G
CM000678.2:g.68829754C>G
NC_000016.9:g.68863657C>G
CM000678.1:g.68863657C>G
NC_000016.8:g.67421158C>G
NG_008021.1:g.97463C>G
ENST00000261769.10:c.2396C>G
ENST00000261769.9:c.2396C>G
ENST00000422392.6:c.2213C>G
ENST00000562118.1:n.614C>G
ENST00000562836.5:n.2467C>G
ENST00000566510.5:c.*1062C>G
ENST00000566612.5:c.*636C>G
ENST00000611625.4:c.2459C>G
ENST00000612417.4:c.1853+3200C>G
ENST00000621016.4:c.1866-4449C>G
NM_004360.3:c.2396C>G
NM_001317184.1:c.2213C>G
NM_001317185.1:c.848C>G
NM_001317186.1:c.431C>G
NM_004360.5:c.2396C>G
NM_001317184.2:c.2213C>G
NM_001317185.2:c.848C>G
NM_001317186.2:c.431C>G
More

Uncertain Significance

Met criteria codes 1
PM2_Supporting
Not Met criteria codes 25
BS2 BS1 BS4 BS3 BP4 BP3 BP1 BP2 BP5 BP7 PS1 PS2 PS3 PS4 PP1 PP2 PP3 PP4 PVS1 PM1 PM3 PM5 PM4 PM6 BA1

Evidence Links 3

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.2396C>G (p.Pro799Arg) variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is no other supporting data that meet criteria for consideration. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting.
Met criteria codes
PM2_Supporting
absent in the gnomAD cohort
Not Met criteria codes
BS2
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
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
Conflicting functional studies
No increased cell motility due to Pro799Arg compared to WT or other missense variants tested. Also immunofluorescence microscopy indicate EGFR activation pattern for Pro799Arg was also similar to WT. PubMed:19268661
Cell aggregation and Matrigel invasion assay using transfected cells suggests Pro799Arg has a pathogenic effect: Pro799Arg transfected cells fail to aggregate and are more invasive into Matrigel. PubMed:15173255
P799R CDH1 has reduced staining at the plasma membrane and increased cytoplasmic accumulation. CDH1/PIPKIγ association is decreased for P799R, but not CDH1/p120 or CDH1/B-catenin association. Cell adhesion and invasion assays indicate P799R transfected cells form smaller aggregates but only slightly more invasive than WT PubMed:22850631
BP4
SIFT, PolyPhen2-HVAR, LRT, MutationTaster, MutationAssessor, PROVEAN, and MetaLR predict deleterious. FATHMM, MetaSVM, and CADD predict tolerated. HSF predicts "Alteration of an exonic ESE site. Potential alteration of splicing." No change predicted by NNSPLICE.
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
BP2
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
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
Conflicting functional studies
No increased cell motility due to Pro799Arg compared to WT or other missense variants tested. Also immunofluorescence microscopy indicate EGFR activation pattern for Pro799Arg was also similar to WT. PubMed:19268661
Cell aggregation and Matrigel invasion assay using transfected cells suggests Pro799Arg has a pathogenic effect: Pro799Arg transfected cells fail to aggregate and are more invasive into Matrigel. PubMed:15173255
P799R CDH1 has reduced staining at the plasma membrane and increased cytoplasmic accumulation. CDH1/PIPKIγ association is decreased for P799R, but not CDH1/p120 or CDH1/B-catenin association. Cell adhesion and invasion assays indicate P799R transfected cells form smaller aggregates but only slightly more invasive than WT PubMed:22850631
PS4
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
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
SIFT, PolyPhen2-HVAR, LRT, MutationTaster, MutationAssessor, PROVEAN, and MetaLR predict deleterious. FATHMM, MetaSVM, and CADD predict tolerated. HSF predicts "Alteration of an exonic ESE site. Potential alteration of splicing." No change predicted by NNSPLICE.
PP4
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
PM1
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
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
PM6
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
Curation History
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