NM_004360.5(CDH1):c.2398C>T (p.Arg800Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 17, 2024
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:: RCV000130753.16

Allele description [Variation Report for NM_004360.5(CDH1):c.2398C>T (p.Arg800Cys)]

NM_004360.5(CDH1):c.2398C>T (p.Arg800Cys)

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.2398C>T (p.Arg800Cys)

HGVS:

NC_000016.10:g.68829756C>T
NG_008021.1:g.97465C>T
NM_001317184.2:c.2215C>T
NM_001317185.2:c.850C>T
NM_001317186.2:c.433C>T
NM_004360.5:c.2398C>TMANE SELECT
NP_001304113.1:p.Arg739Cys
NP_001304114.1:p.Arg284Cys
NP_001304115.1:p.Arg145Cys
NP_004351.1:p.Arg800Cys
LRG_301t1:c.2398C>T
LRG_301:g.97465C>T
NC_000016.9:g.68863659C>T
NM_004360.3:c.2398C>T
NM_004360.4:c.2398C>T
p.R800C

Protein change:

R145C

Links:

dbSNP: rs587782162

NCBI 1000 Genomes Browser:

rs587782162

Molecular consequence:

NM_001317184.2:c.2215C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001317185.2:c.850C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001317186.2:c.433C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.2398C>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
SCV000185644	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 17, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27978560, 29752822, 36436516 Citation Link,
SCV000904072	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 13, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25186627, 27978560, 29752822, 36436516, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185644

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jun 17, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000904072

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 13, 2023)

germline

clinical testing

PubMed (5)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.

Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR.

Cancer. 2015 Jan 1;121(1):25-33. doi: 10.1002/cncr.29010. Epub 2014 Sep 3.

PubMed [citation]

PMID:: 25186627

Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer.

Pearlman R, Frankel WL, Swanson B, Zhao W, Yilmaz A, Miller K, Bacher J, Bigley C, Nelsen L, Goodfellow PJ, Goldberg RM, Paskett E, Shields PG, Freudenheim JL, Stanich PP, Lattimer I, Arnold M, Liyanarachchi S, Kalady M, Heald B, Greenwood C, Paquette I, et al.

JAMA Oncol. 2017 Apr 1;3(4):464-471. doi: 10.1001/jamaoncol.2016.5194.

PubMed [citation]

PMID:: 27978560
PMCID:: PMC5564179

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000185644.10

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

Description

The p.R800C variant (also known as c.2398C>T), located in coding exon 15 of the CDH1 gene, results from a C to T substitution at nucleotide position 2398. The arginine at codon 800 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in 1/450 patients with colorectal cancer diagnosed under the age of 50 years who underwent multi-gene panel testing (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). This alteration has also been reported in 1/937 consecutive Chinese breast cancer patients who underwent multi-gene panel testing (Li JY et al. Int. J. Cancer, 2019 01;144:281-289). This alteration has also been reported in two breast cancer-only families in a genotype-first study of families with CDH1 variants (Garcia-Pelaez J et al. Lancet Oncol, 2023 Jan;24:91-106). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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

From Color Diagnostics, LLC DBA Color Health, SCV000904072.4

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

Description

This missense variant replaces arginine with cysteine at codon 800 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 27978560) and breast cancer (PMID: 25186627, 29752822). This variant has also been reported in unaffected individuals with a family history of breast cancer (PMID: 36436516). This variant has also been identified in 2/251410 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

Last Updated: Oct 13, 2024

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