NM_004360.5(CDH1):c.731A>G (p.Asp244Gly) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 20, 2019
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000486442.8

Allele description [Variation Report for NM_004360.5(CDH1):c.731A>G (p.Asp244Gly)]

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

Gene:

CDH1:cadherin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q22.1

Genomic location:

Preferred name:

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

Other names:

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

HGVS:

NC_000016.10:g.68810240A>G
NG_008021.1:g.77949A>G
NM_001317184.2:c.731A>G
NM_001317185.2:c.-885A>G
NM_001317186.2:c.-1089A>G
NM_004360.5:c.731A>GMANE SELECT
NP_001304113.1:p.Asp244Gly
NP_004351.1:p.Asp244Gly
LRG_301t1:c.731A>G
LRG_301:g.77949A>G
NC_000016.9:g.68844143A>G
NM_004360.3:c.731A>G
NM_004360.4:c.731A>G

Protein change:

D244G

Links:

dbSNP: rs1064794231

NCBI 1000 Genomes Browser:

rs1064794231

Molecular consequence:

NM_001317185.2:c.-885A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-1089A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.731A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.731A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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SLC37A4 [Mesitornis unicolor]
SLC37A4 [Mesitornis unicolor]
Gene ID:104534054

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000568306	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Sep 25, 2018)	germline	clinical testing	Citation Link,
SCV001470283	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Likely pathogenic (Sep 20, 2019)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 26182300, 22470475, 22225527, 10319582, 27582386, 28301459, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000568306

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Sep 25, 2018)

germline

clinical testing

Citation Link,

SCV001470283

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Likely pathogenic
(Sep 20, 2019)

unknown

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond.

Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H, Schrader KA, Schaeffer DF, Shumansky K, Zogopoulos G, Santos TA, Claro I, Carvalho J, Nielsen C, Padilla S, Lum A, Talhouk A, Baker-Lange K, Richardson S, Lewis I, Lindor NM, Pennell E, et al.

JAMA Oncol. 2015 Apr;1(1):23-32. doi: 10.1001/jamaoncol.2014.168. Erratum in: JAMA Oncol. 2015 Apr;1(1):110. doi: 10.1001/jamaoncol.2015.0410.

PubMed [citation]

PMID:: 26182300

E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer.

Simões-Correia J, Figueiredo J, Lopes R, Stricher F, Oliveira C, Serrano L, Seruca R.

PLoS One. 2012;7(3):e33783. doi: 10.1371/journal.pone.0033783. Epub 2012 Mar 21.

PubMed [citation]

PMID:: 22470475
PMCID:: PMC3309996

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV000568306.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001470283.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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