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]

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Variant: NM_004360.5(CDH1):c.-50C>G

CA10577530

234282 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 40774eec-8643-4d45-a466-cb4a0e3ff3bf

Approved on: 2023-08-21

Published on: 2023-08-21

HGVS expressions

NM_004360.5:c.-50C>G

NM_004360.5(CDH1):c.-50C>G

NC_000016.10:g.68737366C>G

CM000678.2:g.68737366C>G

NC_000016.9:g.68771269C>G

CM000678.1:g.68771269C>G

NC_000016.8:g.67328770C>G

NG_008021.1:g.5075C>G

ENST00000261769.10:c.-50C>G

ENST00000261769.9:c.-50C>G

ENST00000422392.6:c.-50C>G

ENST00000566510.5:c.-50C>G

ENST00000566612.5:c.-50C>G

ENST00000611625.4:c.-50C>G

ENST00000612417.4:c.-50C>G

ENST00000621016.4:c.-50C>G

NM_004360.3:c.-50C>G

NM_001317184.1:c.-50C>G

NM_001317185.1:c.-1665C>G

NM_001317186.1:c.-1869C>G

NM_004360.4:c.-50C>G

NM_001317184.2:c.-50C>G

NM_001317185.2:c.-1665C>G

NM_001317186.2:c.-1869C>G

Uncertain Significance

PM2_Supporting

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

Evidence Links 2

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.-50C>G variant occurs in the 5'UTR. This variant is absent in the gnomAD cohort (PM2_Supporting; https://gnomad.broadinstitute.org); however, this variant occurs in a low complexity region of the reference genome version GRCh37/hg19. To our knowledge, the c.-50C>G variant has not been reported in the literature. Other single nucleotide variants in the CDH1 promoter have been shown to alter promoter activity, the c.-49G>T variant slightly increasing activity and the c.-54G>C variant decreasing activity based on luciferase assays (PMID: 23431106, 11996968). In summary, this variant is classified as a variant of uncertain significance based on insufficient ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting.

PM2_Supporting

This variant has not been observed in the gnomAD cohort.

PS2

To our knowledge, this variant has not been reported as de novo.

PS4

To our knowledge, this variant has not been reported in individuals meeting IGCLC criteria for HDGC.

PS3

PS3 can only be applied to splicing variants. Functional studies have suggested that certain variants in the CDH1 promoter may alter transcriptional activity; however, the -50C>T variant has not been evaluated.

Luciferase reporter assays demonstrated that the -288delT and -54G>C variants reduce promoter activity. PubMed:11996968

Luciferase reporter assay demonstrated that the -49G>T variant increases promoter activity by around 33%. PubMed:23431106

PS1

PS1 does not apply to this variant.

PP4

PP4 does not apply to CDH1.

PP1

To our knowledge, this variant has not been reported in individuals meeting IGCLC criteria for HDGC.

PP3

PP3 can only be applied to non-canonical splicing variants.

PP2

PP2 does not apply to CDH1.

PM6

To our knowledge, this variant has not been reported as de novo.

PM3

PM3 does not apply to CDH1.

PM1

PM1 does not apply to CDH1.

PM4

PM4 does not apply to this variant.

PM5

PM5 does not apply to CDH1.

PVS1

PVS1 does not apply to this variant.

BA1

This variant has not been observed in the gnomAD cohort.

BS4

To our knowledge, this variant has not been reported in individuals meeting IGCLC criteria for HDGC.

BS3

BS3 can only be applied to splicing variants. Functional studies have suggested that certain variants in the CDH1 promoter may alter transcriptional activity; however, the -50C>T variant has not been evaluated.

Luciferase reporter assays demonstrated that the -288delT and -54G>C variants reduce promoter activity. PubMed:11996968

Luciferase reporter assay demonstrated that the -49G>T variant increases promoter activity by around 33%. PubMed:23431106

BS1

This variant has not been observed in the gnomAD cohort.

BS2

This variant has been identified in two individuals who do not meet IGCLC criteria for HDGC (GeneDx).

BP5

To our knowledge, this variant has not been reported in a case with an alternate molecular basis for disease.

BP7

BP7 does not apply to this variant.

BP2

To our knowledge, this variant has not been observed in cis or trans with a pathogenic variant.

BP3

BP3 does not apply to CDH1.

BP4

BP4 does not apply to this variant.

BP1

BP1 does not apply to CDH1.

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