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_004360.5(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
Approved on: 2023-08-17
Published on: 2023-08-17

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
More

Likely Benign

Met criteria codes 2
PM2_Supporting BS2
Not Met criteria codes 24
BA1 PM1 PM3 PM5 PM4 PM6 BS1 BS4 BS3 BP4 BP3 BP1 BP2 BP5 BP7 PVS1 PS1 PS2 PS3 PS4 PP1 PP2 PP3 PP4

Evidence Links 0

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.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has been observed in more than 30 families without DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2; unpublished).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
PM2_Supporting
This variant has a frequency of 6.57x10-6 (1 in 152,170 alleles) in gnomAD v3.1.1.
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).
Not Met criteria codes
BA1
This variant has a frequency of 6.57x10-6 (1 in 152,170 alleles) in gnomAD v3.1.1.
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.
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).
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.
PVS1
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.
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.
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.