NM_004360.5(CDH1):c.268C>T (p.Arg90Trp) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Oct 9, 2023
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:: RCV000160382.14

Allele description [Variation Report for NM_004360.5(CDH1):c.268C>T (p.Arg90Trp)]

NM_004360.5(CDH1):c.268C>T (p.Arg90Trp)

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.268C>T (p.Arg90Trp)

Other names:

p.R90W:CGG>TGG

HGVS:

NC_000016.10:g.68801774C>T
NG_008021.1:g.69483C>T
NM_001317184.2:c.268C>T
NM_001317185.2:c.-1348C>T
NM_001317186.2:c.-1552C>T
NM_004360.5:c.268C>TMANE SELECT
NP_001304113.1:p.Arg90Trp
NP_004351.1:p.Arg90Trp
LRG_301t1:c.268C>T
LRG_301:g.69483C>T
NC_000016.9:g.68835677C>T
NM_004360.3:c.268C>T
NM_004360.4:c.268C>T
p.R90W

Protein change:

R90W

Links:

dbSNP: rs730881661

NCBI 1000 Genomes Browser:

rs730881661

Molecular consequence:

NM_001317185.2:c.-1348C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-1552C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.268C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.268C>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
SCV000213297	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Jun 6, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23555086, 33471991 Citation Link,
SCV000904698	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 9, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23555086, 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000213297

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Jun 6, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000904698

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 9, 2023)

germline

clinical testing

PubMed (3)
[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

Molecular and survival differences between familial and sporadic gastric cancers.

Fang WL, Chang SC, Lan YT, Huang KH, Lo SS, Li AF, Chi CW, Wu CW, Chiou SH.

Biomed Res Int. 2013;2013:396272. doi: 10.1155/2013/396272. Epub 2013 Mar 5.

PubMed [citation]

PMID:: 23555086
PMCID:: PMC3603157

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000213297.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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, SCV000904698.5

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

Description

This missense variant replaces arginine with tryptophan at codon 90 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with familial gastric cancer in the literature (PMID: 23555086). In a large breast cancer case-control study, this variant was identified in 4/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 1/251338 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: Sep 29, 2024

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