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

gnomAD frequency: 0.00001  dbSNP: rs1064794231

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328358	SCV004035117	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-17	reviewed by expert panel	curation	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has been observed in more than 30 families without DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2; unpublished).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.
GeneDx	RCV000486442	SCV000568306	uncertain significance	not provided	2018-09-25	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.731A>G at the cDNA level, p.Asp244Gly (D244G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant was observed in at least one individual with a personal and family history of gastric cancer (Yoon 1999). Functional studies suggest that this variant may result in decreased adhesion, increased migration, and loss of E-cadherin cytoplasmic membrane localization compared to wild type (Petrova 2016, Ghoumid 2017). CDH1 Asp244Gly was not observed in large population cohorts (Lek 2016). This variant is located in the Cadherin 1 domain (Brooks-Wilson 2004, Figueiredo 2013, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CDH1 Asp244Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000568819	SCV000666324	likely benign	Hereditary cancer-predisposing syndrome	2023-06-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000698453	SCV000827118	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000568819	SCV000911957	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-08	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 244 of the CDH1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Functional studies reported this variant to be partially functional in cell adhesion, migration and subcellular localization (PMID: 27582386, 28301459). This variant has been reported in an individual affected with gastric cancer with positive family history of the disease (PMID: 10319582). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486442	SCV001470283	likely pathogenic	not provided	2019-09-20	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0000066 (1/152170 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with gastric cancer (PMIDs: 10319582 (1999)). Functional studies state that the variant results in loss of cytoplasmic membrane localization (PMID: 28301459 (2017)), as well as inhibits basic E-cadherin adhesion function (PMID: 27582386 (2016)), and is considered destabilizing (PMID: 22470475 (2012)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics	RCV003464005	SCV004215651	uncertain significance	Familial cancer of breast	2023-09-05	criteria provided, single submitter	clinical testing