NM_004360.5(CDH1):c.1711+2_1711+7del AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Aug 15, 2022
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:: RCV000166240.8

Allele description [Variation Report for NM_004360.5(CDH1):c.1711+2_1711+7del]

NM_004360.5(CDH1):c.1711+2_1711+7del

Gene:

CDH1:cadherin 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

16q22.1

Genomic location:

Preferred name:

NM_004360.5(CDH1):c.1711+2_1711+7del

HGVS:

NC_000016.10:g.68819427_68819432del
NG_008021.1:g.87136_87141del
NM_001317184.2:c.1528+2_1528+7del
NM_001317185.2:c.163+2_163+7del
NM_001317186.2:c.-254-2574_-254-2569del
NM_004360.5:c.1711+2_1711+7delMANE SELECT
LRG_301t1:c.1711+2_1711+7del
LRG_301:g.87136_87141del
NC_000016.10:g.68819427_68819432delTAAGGG
NC_000016.9:g.68853328_68853333del
NC_000016.9:g.68853330_68853335del
NM_004360.3:c.1711+2_1711+7del
NM_004360.3:c.1711+2_1711+7delTAAGGG
NM_004360.4(CDH1):c.1711+2_1711+7delTAAGGG
NM_004360.4:c.1711+2_1711+7del

Links:

dbSNP: rs786203089

NCBI 1000 Genomes Browser:

rs786203089

Molecular consequence:

NM_001317186.2:c.-254-2574_-254-2569del - intron variant - [Sequence Ontology: SO:0001627]
NM_001317184.2:c.1528+2_1528+7del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001317185.2:c.163+2_163+7del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_004360.5:c.1711+2_1711+7del - splice donor variant - [Sequence Ontology: SO:0001575]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000217020	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Nov 10, 2017)	germline	clinical testing	Citation Link,
SCV002052140	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 15, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32133419, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000217020

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Nov 10, 2017)

germline

clinical testing

Citation Link,

SCV002052140

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 15, 2022)

germline

clinical testing

PubMed (2)
[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

Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes.

Landrith T, Li B, Cass AA, Conner BR, LaDuca H, McKenna DB, Maxwell KN, Domchek S, Morman NA, Heinlen C, Wham D, Koptiuch C, Vagher J, Rivera R, Bunnell A, Patel G, Geurts JL, Depas MM, Gaonkar S, Pirzadeh-Miller S, Krukenberg R, Seidel M, et al.

NPJ Precis Oncol. 2020;4:4. doi: 10.1038/s41698-020-0109-y.

PubMed [citation]

PMID:: 32133419
PMCID:: PMC7039900

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

Details of each submission

From Ambry Genetics, SCV000217020.7

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

Description

The c.1711+2_1711+7delTAAGGG intronic pathogenic mutation results from a deletion of 6 nucleotides at positions c.1711+2 to c.1711+7 after coding exon 11 of the CDH1 gene. This alteration was previously identified in a HDGC family, and subsequent RNA analyses demonstrated abnormal splicing (Ambry internal data). In addition, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified 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, SCV002052140.2

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

Description

This variant causes the deletion of 6 nucleotides in the canonical splice donor region in intron 11 of the CDH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA functional studies have reported that this variant causes increased skipping of exon 11. Baseline exon 11 skipping in healthy control cells was also observed (PMID: 32133419). Skipping of CDH1 exon 11 is expected to create a premature translation stop signal and result in an absent or non-functional protein product. This variant has been reported in an individual affected with diffuse gastric cancer (External lab communication). 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 Likely 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

ClinVar

Relating variation to medicine