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

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

Approved on: 2023-08-03

Published on: 2023-08-03

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:c.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

• Met criteria codes: BS2_Stand Alone PM2_Supporting

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

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1

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has been observed in more than 30 families without DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2; unpublished).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.

Met criteria codes

• BS2_Stand Alone: 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.

Not Met criteria codes

• BP4: BP4 is not applicable for missense variants in CDH1.
• BP3: BP3 is not applicable for CDH1.
• BP1: BP1 is not applicable for CDH1.
• BP2: The c.731A>G variant has not been reported in cis or trans with a pathogenic variant.
• BP5: The c.731A>G variant has not been reported in a case with an alternate molecular basis for disease.
• BP7: BP7 is not applicable for missense variants.
• PS1: PS1 is not applicable for CDH1.
• PS2: The c.731A>G variant has not been reported as assumed or confirmed de novo.
• 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).
• 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.
• BA1: This variant has a frequency of 6.57x10-6 (1 in 152,170 alleles) in gnomAD v3.1.1.
• PP1: Segregation analysis of the c.731A>G variant in HDGC families has not been reported.
• PP2: PP2 is not applicable for CDH1.
• PP3: PP3 is not applicable for missense variants in CDH1.
• PP4: PP4 is not applicable for CDH1.
• PM1: PM1 is not applicable for CDH1.
• PM3: PM3 is not applicable for CDH1.
• PM5: PM5 is not applicable for missense variants in CDH1.
• PM4: PM4 is not applicable for missense variants.
• PM6: The c.731A>G variant has not been reported as assumed or confirmed de novo.
• PVS1: BP7 is not applicable for missense variants.
• BS1: This variant has a frequency of 6.57x10-6 (1 in 152,170 alleles) in gnomAD v3.1.1.
• 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).