NM_004360.5(CDH1):c.1711+1dup AND Hereditary diffuse gastric adenocarcinoma

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 14, 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:: RCV001384616.9

Allele description [Variation Report for NM_004360.5(CDH1):c.1711+1dup]

NM_004360.5(CDH1):c.1711+1dup

Gene:

CDH1:cadherin 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

16q22.1

Genomic location:

Preferred name:

NM_004360.5(CDH1):c.1711+1dup

HGVS:

NC_000016.10:g.68819426dup
NG_008021.1:g.87135dup
NM_001317184.2:c.1528+1dup
NM_001317185.2:c.163+1dup
NM_001317186.2:c.-254-2575dup
NM_004360.5:c.1711+1dupMANE SELECT
LRG_301:g.87135dup
NC_000016.9:g.68853327_68853328insG
NC_000016.9:g.68853329dup

Note:

ClinGen staff contributed the HGVS expression for this variant.

Nucleotide change:

1-BP INS, 1711G

Links:

OMIM: 192090.0013; dbSNP: rs2152137028

NCBI 1000 Genomes Browser:

rs2152137028

Molecular consequence:

NM_001317186.2:c.-254-2575dup - intron variant - [Sequence Ontology: SO:0001627]
NM_001317184.2:c.1528+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001317185.2:c.163+1dup - splice donor variant - [Sequence Ontology: SO:0001575]
NM_004360.5:c.1711+1dup - splice donor variant - [Sequence Ontology: SO:0001575]

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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Homo sapiens general transcription factor IIB (GTF2B), mRNA
Homo sapiens general transcription factor IIB (GTF2B), mRNA
gi|52426766|ref|NM_001514.3|

Nucleotide
RecName: Full=Paired box protein Pax-1; AltName: Full=HuP48
RecName: Full=Paired box protein Pax-1; AltName: Full=HuP48
gi|296439493|sp|P15863.4|PAX1_HUMAN

Protein
OR6A2 olfactory receptor family 6 subfamily A member 2 [Homo sapiens]
OR6A2 olfactory receptor family 6 subfamily A member 2 [Homo sapiens]
Gene ID:8590

Gene
8590[uid] AND (alive[prop]) (1)
Gene
LOC117432365 [Acipenser ruthenus]
LOC117432365 [Acipenser ruthenus]
Gene ID:117432365

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001584183	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15235021, 20373070, 9751616, 11419427, 28492532
SCV004043652	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Jun 14, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001584183

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 31, 2020)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004043652

Myriad Genetics, Inc.

criteria provided, single submitter

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

Likely pathogenic
(Jun 14, 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

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

Hereditary diffuse gastric cancer: translation of CDH1 germline mutations into clinical practice.

Guilford P, Humar B, Blair V.

Gastric Cancer. 2010 Mar;13(1):1-10. doi: 10.1007/s10120-009-0531-x. Epub 2010 Apr 7. Review.

PubMed [citation]

PMID:: 20373070

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV001584183.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant has been observed in individual(s) with diffuse gastric cancer (PMID: 9751616, 11419427). It has also been observed to segregate with disease in related individuals. This variant is also known as 1711insG in the literature. ClinVar contains an entry for this variant (Variation ID: 12242). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser572Phefs*16) in the CDH1 gene. It is expected to result in an absent or disrupted protein product.

#	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., SCV004043652.2

#	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.

#	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: Jul 7, 2024

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