NM_004360.5(CDH1):c.220C>T (p.Arg74Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 22, 2021
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:: RCV000567709.10

Allele description [Variation Report for NM_004360.5(CDH1):c.220C>T (p.Arg74Ter)]

NM_004360.5(CDH1):c.220C>T (p.Arg74Ter)

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.220C>T (p.Arg74Ter)

HGVS:

NC_000016.10:g.68801726C>T
NG_008021.1:g.69435C>T
NM_001317184.2:c.220C>T
NM_001317185.2:c.-1396C>T
NM_001317186.2:c.-1600C>T
NM_004360.5:c.220C>TMANE SELECT
NP_001304113.1:p.Arg74Ter
NP_004351.1:p.Arg74Ter
LRG_301t1:c.220C>T
LRG_301:g.69435C>T
NC_000016.9:g.68835629C>T
NM_004360.3:c.220C>T
NM_004360.4(CDH1):c.220C>T
NM_004360.4:c.220C>T
p.Arg74Ter

Protein change:

R74*

Links:

dbSNP: rs876658932

NCBI 1000 Genomes Browser:

rs876658932

Molecular consequence:

NM_001317185.2:c.-1396C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-1600C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.220C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_004360.5:c.220C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000661607	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Nov 22, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25123297, 30287823, 32842532, 33471991 Citation Link,
SCV001356424	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 15, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000661607

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Nov 22, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001356424

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 15, 2020)

germline

clinical testing

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

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

Tumor genome analysis includes germline genome: are we ready for surprises?

Catenacci DV, Amico AL, Nielsen SM, Geynisman DM, Rambo B, Carey GB, Gulden C, Fackenthal J, Marsh RD, Kindler HL, Olopade OI.

Int J Cancer. 2015 Apr 1;136(7):1559-67. doi: 10.1002/ijc.29128. Epub 2014 Aug 14.

PubMed [citation]

PMID:: 25123297
PMCID:: PMC4303936

Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.

Momozawa Y, Iwasaki Y, Parsons MT, Kamatani Y, Takahashi A, Tamura C, Katagiri T, Yoshida T, Nakamura S, Sugano K, Miki Y, Hirata M, Matsuda K, Spurdle AB, Kubo M.

Nat Commun. 2018 Oct 4;9(1):4083. doi: 10.1038/s41467-018-06581-8.

PubMed [citation]

PMID:: 30287823
PMCID:: PMC6172276

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000661607.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.R74* pathogenic mutation (also known as c.220C>T), located in coding exon 3 of the CDH1 gene, results from a C to T substitution at nucleotide position 220. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation was detected in a patient with gastric cancer diagnosed at age 41 (Llach J et al. Cancers (Basel), 2020 Aug;12). In one study, this variant was observed in 1/7,051 unselected female breast cancer patients and 0/11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). In another study, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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, SCV001356424.2

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

Description

This variant changes 1 nucleotide in exon 3 of the CDH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

#	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: Sep 29, 2024

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