NM_004360.5(CDH1):c.2398C>T (p.Arg800Cys) AND Hereditary diffuse gastric adenocarcinoma

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Dec 6, 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:: RCV000204619.18

Allele description [Variation Report for NM_004360.5(CDH1):c.2398C>T (p.Arg800Cys)]

NM_004360.5(CDH1):c.2398C>T (p.Arg800Cys)

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.2398C>T (p.Arg800Cys)

HGVS:

NC_000016.10:g.68829756C>T
NG_008021.1:g.97465C>T
NM_001317184.2:c.2215C>T
NM_001317185.2:c.850C>T
NM_001317186.2:c.433C>T
NM_004360.5:c.2398C>TMANE SELECT
NP_001304113.1:p.Arg739Cys
NP_001304114.1:p.Arg284Cys
NP_001304115.1:p.Arg145Cys
NP_004351.1:p.Arg800Cys
LRG_301t1:c.2398C>T
LRG_301:g.97465C>T
NC_000016.9:g.68863659C>T
NM_004360.3:c.2398C>T
NM_004360.4:c.2398C>T
p.R800C

Protein change:

R145C

Links:

dbSNP: rs587782162

NCBI 1000 Genomes Browser:

rs587782162

Molecular consequence:

NM_001317184.2:c.2215C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001317185.2:c.850C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001317186.2:c.433C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.2398C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000260231	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 6, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25186627, 27978560, 29752822, 28492532
SCV000784761	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Nov 13, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25186627, 27978560 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV001749934	GenomeConnect - Invitae Patient Insights Network	no classification provided	not provided	unknown	phenotyping only
SCV003926935	European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto - ERN GENTURIS	criteria provided, single submitter (Lee et al. (Hum Mutat. 2018))	Uncertain significance (Aug 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30311375, 36436516
SCV004019597	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Uncertain significance (Mar 6, 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	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, phenotyping only
not provided	germline	no	not provided	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer.

Li JY, Jing R, Wei H, Wang M, Xiaowei Q, Liu H, Jian L, Ou JH, Jiang WH, Tian FG, Sheng Y, Li HY, Xu H, Zhang RS, Guan AH, Liu K, Jiang HC, Ren Y, He JJ, Huang W, Liao N, Cai X, et al.

Int J Cancer. 2019 Jan 15;144(2):281-289. doi: 10.1002/ijc.31601. Epub 2018 Nov 8.

PubMed [citation]

PMID:: 29752822

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

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000260231.10

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

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 800 of the CDH1 protein (p.Arg800Cys). This variant is present in population databases (rs587782162, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer and/or colorectal cancer (PMID: 25186627, 27978560, 29752822). ClinVar contains an entry for this variant (Variation ID: 141990). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.

#	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 Counsyl, SCV000784761.2

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

#	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 GenomeConnect - Invitae Patient Insights Network, SCV001749934.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant interpreted as Uncertain significance and reported on 02-14-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

#	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 European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto - ERN GENTURIS, SCV003926935.1

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

Description

"2 families not fulfilling 2020 HDGC criteria-Familial history of breast cancer"

PubMed [ID: 36436516]

Description

PM2; BS2_Supporting (PMID: 30311375)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	2	not provided

From Myriad Genetics, Inc., SCV004019597.1

#	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 classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

#	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 13, 2024

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