NM_004360.5(CDH1):c.2594G>A (p.Trp865Ter) AND Hereditary diffuse gastric adenocarcinoma

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 25, 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:: RCV000662745.8

Allele description [Variation Report for NM_004360.5(CDH1):c.2594G>A (p.Trp865Ter)]

NM_004360.5(CDH1):c.2594G>A (p.Trp865Ter)

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.2594G>A (p.Trp865Ter)

HGVS:

NC_000016.10:g.68833444G>A
NG_008021.1:g.101153G>A
NM_001317184.2:c.2411G>A
NM_001317185.2:c.1046G>A
NM_001317186.2:c.629G>A
NM_004360.5:c.2594G>AMANE SELECT
NP_001304113.1:p.Trp804Ter
NP_001304114.1:p.Trp349Ter
NP_001304115.1:p.Trp210Ter
NP_004351.1:p.Trp865Ter
LRG_301t1:c.2594G>A
LRG_301:g.101153G>A
NC_000016.9:g.68867347G>A
NC_000016.9:g.68867347G>A
NM_004360.3:c.2594G>A
NM_004360.4(CDH1):c.2594G>A
p.Trp865Ter

Protein change:

W210*

Links:

dbSNP: rs1555518270

NCBI 1000 Genomes Browser:

rs1555518270

Molecular consequence:

NM_001317184.2:c.2411G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001317185.2:c.1046G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001317186.2:c.629G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_004360.5:c.2594G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hereditary diffuse gastric adenocarcinoma (HDGC)
Synonyms:: Hereditary diffuse gastric cancer
Identifiers:: MONDO: MONDO:0007648; MedGen: C1708349; Orphanet: 26106; OMIM: 137215

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000785524	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Nov 14, 2017)	unknown	clinical testing	Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV002227614	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 25, 2021)	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

SCV000785524

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Uncertain significance
(Nov 14, 2017)

unknown

clinical testing

Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf,

Citation Link,

SCV002227614

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 25, 2021)

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Counsyl, SCV000785524.2

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002227614.4

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 496819). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the CDH1 gene (p.Trp865*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acids of the CDH1 protein.

#	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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