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_004360.5(CDH1):c.731A>G (p.Asp244Gly)

CA16620242

420005 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 83e69ab0-c479-45dc-9b25-e40a7ad48793

HGVS expressions

NM_004360.5:c.731A>G

NM_004360.5(CDH1):c.731A>G (p.Asp244Gly)

NC_000016.10:g.68810240A>G

CM000678.2:g.68810240A>G

NC_000016.9:g.68844143A>G

CM000678.1:g.68844143A>G

NC_000016.8:g.67401644A>G

NG_008021.1:g.77949A>G

ENST00000261769.10:c.731A>G

ENST00000261769.9:c.731A>G

ENST00000422392.6:c.731A>G

ENST00000561751.1:n.454+1392A>G

ENST00000562836.5:n.802A>G

ENST00000566510.5:c.575A>G

ENST00000566612.5:c.731A>G

ENST00000611625.4:c.731A>G

ENST00000612417.4:c.731A>G

ENST00000621016.4:c.731A>G

NM_004360.3:c.731A>G

NM_001317184.1:c.731A>G

NM_001317185.1:c.-885A>G

NM_001317186.1:c.-1089A>G

NM_004360.4:c.731A>G

NM_001317184.2:c.731A>G

NM_001317185.2:c.-885A>G

NM_001317186.2:c.-1089A>G

Likely Benign

BS2 PM2_Supporting

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

Evidence Links 0

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.731A>G (p.Asp244Gly) variant results in a non-conservative amino acid substitution in the Cadherin-1 domain. This variant has a frequency of 6.57x10-6 (1 in 152,170 alleles) in gnomAD (PM2_supporting) and has been reported in one family meeting IGCLC criteria for HDGC (PMID: 10319582). However, this variant has been observed in more than 30 families without DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2; unpublished). Functional studies of the p.Asp244Gly variant suggest that this variant may affect the subcellular localization of E-cadherin and regulation of cell adhesion (PMID: 27582386, 28301459). In summary, this variant is classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2, PM2_supporting.

BS2

The c.731A>G variant has been observed in 37 individuals without DGC, LBC or SRC tumours and whose families do not suggest HDGC (Ambry, GeneDx, Invitae).

PM2_Supporting

This variant has a frequency of 6.57x10-6 (1 in 152,170 alleles) in gnomAD v3.1.1.

PS2

The c.731A>G variant has not been reported as assumed or confirmed de novo.

PS4

The c.731A>G (p.Asp244Gly) variant has been reported in one family meeting IGCLC criteria for HDGC (PMID: 10319582). However, less than 30% of reported individuals meet HDGC criteria. Therefore, PS4_P not met.

PS3

PS3 is not applicable for missense variants in CDH1. Functional studies of the p.Asp244Gly variant suggest that this variant may affect the subcellular localization of E-cadherin and regulation of cell adhesion (PMID: 27582386, 28301459).

PS1

PS1 is not applicable for CDH1.

BP7

BP7 is not applicable for missense variants.

BP5

The c.731A>G variant has not been reported in a case with an alternate molecular basis for disease.

BP3

BP3 is not applicable for CDH1.

BP2

The c.731A>G variant has not been reported in cis or trans with a pathogenic variant.

BP4

BP4 is not applicable for missense variants in CDH1.

BP1

BP1 is not applicable for CDH1.

PP4

PP4 is not applicable for CDH1.

PP1

Segregation analysis of the c.731A>G variant in HDGC families has not been reported.

PP3

PP3 is not applicable for missense variants in CDH1.

PP2

PP2 is not applicable for CDH1.

BA1

This variant has a frequency of 6.57x10-6 (1 in 152,170 alleles) in gnomAD v3.1.1.

PVS1

BP7 is not applicable for missense variants.

PM6

The c.731A>G variant has not been reported as assumed or confirmed de novo.

PM4

PM4 is not applicable for missense variants.

PM3

PM3 is not applicable for CDH1.

PM1

PM1 is not applicable for CDH1.

PM5

PM5 is not applicable for missense variants in CDH1.

BS4

Segregation analysis of the c.731A>G variant in HDGC families has not been reported.

BS3

BS3 is not applicable for missense variants in CDH1. Functional studies of the p.Asp244Gly variant suggest that this variant may affect the subcellular localization of E-cadherin and regulation of cell adhesion (PMID: 27582386, 28301459).

BS1

This variant has a frequency of 6.57x10-6 (1 in 152,170 alleles) in gnomAD v3.1.1.

Approved on: 2023-08-17

Published on: 2023-08-17

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