NM_004360.5(CDH1):c.1565C>T (p.Thr522Ile) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 14, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001174680.4

Allele description [Variation Report for NM_004360.5(CDH1):c.1565C>T (p.Thr522Ile)]

NM_004360.5(CDH1):c.1565C>T (p.Thr522Ile)

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.1565C>T (p.Thr522Ile)

Other names:

NM_004360.5(CDH1):c.1565C>T; p.Thr522Ile

HGVS:

NC_000016.10:g.68815759C>T
NG_008021.1:g.83468C>T
NM_001317184.2:c.1382C>T
NM_001317185.2:c.17C>T
NM_001317186.2:c.-255C>T
NM_004360.5:c.1565C>TMANE SELECT
NP_001304113.1:p.Thr461Ile
NP_001304114.1:p.Thr6Ile
NP_004351.1:p.Thr522Ile
LRG_301t1:c.1565C>T
LRG_301:g.83468C>T
NC_000016.9:g.68849662C>T
NM_004360.3:c.1565C>T
NM_004360.4:c.1565C>T

Protein change:

T461I

Links:

dbSNP: rs863224725

NCBI 1000 Genomes Browser:

rs863224725

Molecular consequence:

NM_001317186.2:c.-255C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.1382C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001317185.2:c.17C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.1565C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001337913	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Mar 14, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 27227907, 29641532, 30287823, 32260281, 25819062 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001337913

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Mar 14, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Variants of the CDH1 (E-Cadherin) Gene Associated with Oral Clefts in the Thai Population.

Ittiwut R, Ittiwut C, Siriwan P, Chichareon V, Suphapeetiporn K, Shotelersuk V.

Genet Test Mol Biomarkers. 2016 Jul;20(7):406-9. doi: 10.1089/gtmb.2015.0325. Epub 2016 May 26.

PubMed [citation]

PMID:: 27227907

Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers.

Pritchard AL, Johansson PA, Nathan V, Howlie M, Symmons J, Palmer JM, Hayward NK.

PLoS One. 2018;13(4):e0194098. doi: 10.1371/journal.pone.0194098.

PubMed [citation]

PMID:: 29641532
PMCID:: PMC5894988

See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001337913.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: CDH1 c.1565C>T (p.Thr522Ile) results in a non-conservative amino acid change located in the Cadherin-like domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.4e-05 in 276562 control chromosomes (gnomAD and publications). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1565C>T has been reported in the literature in an individual affected with nonsyndromic oral clefts (Ittiwu_2016) and an individual affected with ichthyosis vulgaris and atopic dermatitis (Taylan_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) or likely benign/benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.

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

Last Updated: Feb 25, 2025

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