NM_004360.5(CDH1):c.1565C>T (p.Thr522Ile) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 8, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000448662.11

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)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000537599	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 30, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000661630	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27227907, 29641532, 30287823 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000537599

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 30, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000661630

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Mar 8, 2023)

germline

clinical testing

PubMed (3)
[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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

See all PubMed Citations (4)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000537599.5

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

Description

This missense variant replaces threonine with isoleucine at codon 522 of the CDH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251328 chromosomes 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.

#	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

From Ambry Genetics, SCV000661630.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.T522I variant (also known as c.1565C>T), located in coding exon 10 of the CDH1 gene, results from a C to T substitution at nucleotide position 1565. The amino acid change results in threonine to isoleucine at codon 522, an amino acid with similar properties. This alteration was observed in with an allele frequency of 0.00009 in 11241 female controls and was not observed in 7051 unselected female breast cancer patients of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration was also identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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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