NM_004360.5(CDH1):c.2296-2A>G AND Hereditary diffuse gastric adenocarcinoma

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 15, 2023
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:: RCV000639202.12

Allele description [Variation Report for NM_004360.5(CDH1):c.2296-2A>G]

NM_004360.5(CDH1):c.2296-2A>G

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.2296-2A>G

HGVS:

NC_000016.10:g.68829652A>G
NG_008021.1:g.97361A>G
NM_001317184.2:c.2113-2A>G
NM_001317185.2:c.748-2A>G
NM_001317186.2:c.331-2A>G
NM_004360.5:c.2296-2A>GMANE SELECT
LRG_301t1:c.2296-2A>G
LRG_301:g.97361A>G
NC_000016.9:g.68863555A>G
NM_004360.3:c.2296-2A>G
NM_004360.4:c.2296-2A>G

Links:

dbSNP: rs876660393

NCBI 1000 Genomes Browser:

rs876660393

Molecular consequence:

NM_001317184.2:c.2113-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001317185.2:c.748-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001317186.2:c.331-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_004360.5:c.2296-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

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

Recent activity

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RecName: Full=Nck-associated protein 1; Short=NAP 1; AltName: Full=Membrane-asso...
RecName: Full=Nck-associated protein 1; Short=NAP 1; AltName: Full=Membrane-associated protein HEM-2; AltName: Full=p125Nap1
gi|12643947|sp|Q9Y2A7.1|NCKP1_HUMAN

Protein
RecName: Full=Cartilage intermediate layer protein 1; Short=CILP-1; AltName: Ful...
RecName: Full=Cartilage intermediate layer protein 1; Short=CILP-1; AltName: Full=Cartilage intermediate-layer protein; Contains: RecName: Full=Cartilage intermediate layer protein 1 C1; Contains: RecName: Full=Cartilage intermediate layer protein 1 C2; Flags: Precursor
gi|317373560|sp|O75339.4|CILP1_HUMA

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000760771	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 15235021, 20373070, 28492532
SCV004043172	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Jun 15, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000760771

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 25, 2023)

germline

clinical testing

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

SCV004043172

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Likely pathogenic
(Jun 15, 2023)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria.

Brooks-Wilson AR, Kaurah P, Suriano G, Leach S, Senz J, Grehan N, Butterfield YS, Jeyes J, Schinas J, Bacani J, Kelsey M, Ferreira P, MacGillivray B, MacLeod P, Micek M, Ford J, Foulkes W, Australie K, Greenberg C, LaPointe M, Gilpin C, Nikkel S, et al.

J Med Genet. 2004 Jul;41(7):508-17.

PubMed [citation]

PMID:: 15235021
PMCID:: PMC1735838

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000760771.8

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

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 233417). Disruption of this splice site has been observed in individuals with hereditary diffuse gastric cancer (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 14 of the CDH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070).

#	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 Myriad Genetics, Inc., SCV004043172.2

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

Description

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data].

#	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

Last Updated: Oct 8, 2024

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