Evidence Repository - Clinical Genome Resources

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_004360.4(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

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

NM_004360.5(CDH1):c.2396C>G (p.Pro799Arg)

Uncertain Significance

PM2_Supporting

PP4 PP1 PP2 PP3 PM6 PM3 PM1 PM4 PM5 BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP1 BP4 PVS1 PS2 PS4 PS3 PS1 BA1

Evidence Links 3

Expert Panel

CDH1 VCEP

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.

PM2_Supporting

absent in the gnomAD cohort

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

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.

PM6

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

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

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

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

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS2

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

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

PVS1

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

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS3

Conflicting functional studies

PS1

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

Approved on: 2023-08-21

Published on: 2023-08-21

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