VCV000234912.28 - ClinVar

NM_004360.5(CDH1):c.2590G>A (p.Glu864Lys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004360.5(CDH1):c.2590G>A (p.Glu864Lys)

Variation ID: 234912 Accession: VCV000234912.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q22.1 16: 68833440 (GRCh38) [ NCBI UCSC ] 16: 68867343 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 29, 2016	Nov 3, 2024	Oct 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004360.5:c.2590G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004351.1:p.Glu864Lys	missense
NM_001317184.2:c.2407G>A	NP_001304113.1:p.Glu803Lys	missense
NM_001317185.2:c.1042G>A	NP_001304114.1:p.Glu348Lys	missense
NM_001317186.2:c.625G>A	NP_001304115.1:p.Glu209Lys	missense
NC_000016.10:g.68833440G>A
NC_000016.9:g.68867343G>A
NG_008021.1:g.101149G>A
LRG_301:g.101149G>A
LRG_301t1:c.2590G>A

... more HGVS ... less HGVS

Protein change

E864K, E803K, E348K, E209K

Other names

Canonical SPDI

NC_000016.10:68833439:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00004

Links

ClinGen: CA8130311 dbSNP: rs142927667 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CDH1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4645	4739

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Uncertain significance (1)	criteria provided, single submitter	Oct 25, 2024	RCV000216670.5
Hereditary diffuse gastric adenocarcinoma	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 2, 2024	RCV000471203.14
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Sep 11, 2023	RCV000563816.10
Blepharocheilodontic syndrome 1	Uncertain significance (1)	criteria provided, single submitter	Jul 31, 2019	RCV001292691.2
Familial cancer of breast	Uncertain significance (1)	criteria provided, single submitter	Aug 18, 2023	RCV003463623.1
not specified	Uncertain significance (1)	criteria provided, single submitter	Aug 15, 2023	RCV002465577.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (May 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000689520.4 First in ClinVar: Feb 19, 2018 Last updated: Jan 08, 2022	Comment: This missense variant replaces glutamic acid with lysine at codon 864 of the CDH1 protein. To our knowledge, functional studies have not been reported for … (more) This missense variant replaces glutamic acid with lysine at codon 864 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with diffuse gastric cancer or lobular breast cancer in the literature, but has been observed in an individual suspected of Lynch syndrome (PMID 25980754), an individual with colorectal cancer (PMID 27978560), an individual affected with ovarian cancer (PMID 30306255), and an individual with a personal and/or family history of breast and/or ovarian cancer (PMID: 29470806). This variant has been identified in 4/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Jan 02, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary diffuse gastric adenocarcinoma Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000545398.10 First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 28492532‚ 25980754‚ 27978560‚ 29470806‚ 30306255‚ 34326862‚ 36271359 Comment: This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 864 of the CDH1 protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 864 of the CDH1 protein (p.Glu864Lys). This variant is present in population databases (rs142927667, gnomAD 0.006%). This missense change has been observed in individual(s) with various forms of cancer including: colorectal cancer, ovarian cancer, endometrial cancer, breast cancer, giloblastoma, osteosarcoma, and/or clinical features of Lynch syndrome (PMID: 25980754, 27978560, 29470806, 30306255, 34326862, 36271359). ClinVar contains an entry for this variant (Variation ID: 234912). 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. (less)
Uncertain significance (Sep 11, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000661618.6 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 27978560‚ 29470806‚ 30306255‚ 33471991 Comment: The p.E864K variant (also known as c.2590G>A), located in coding exon 16 of the CDH1 gene, results from a G to A substitution at nucleotide … (more) The p.E864K variant (also known as c.2590G>A), located in coding exon 16 of the CDH1 gene, results from a G to A substitution at nucleotide position 2590. The glutamic acid at codon 864 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in individuals from multiple cancer cohorts, including colon cancer, and breast and/or ovarian cancer (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471; Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Bonache S et al. J Cancer Res Clin Oncol, 2018 Dec;144:2495-2513; Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Oct 25, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000279999.13 First in ClinVar: May 29, 2016 Last updated: Nov 03, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with Lynch syndrome-related cancers or breast and/or ovarian cancers (PMID: 30306255, 29470806, 25980754, 27978560, 33471991); This variant is associated with the following publications: (PMID: 25980754, 27978560, 29470806, 30306255, 36271359, 33471991, 15235021, 22850631, 34326862) (less)
Uncertain significance (Jul 31, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Blepharocheilodontic syndrome 1 Affected status: yes Allele origin: paternal	Baylor Genetics Study: CSER-TexasKidsCanSeq Accession: SCV001481302.2 First in ClinVar: Feb 28, 2021 Last updated: Feb 28, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Aug 01, 2022)	criteria provided, single submitter (Lee et al. (Hum Mutat. 2018)) Method: clinical testing	Hereditary diffuse gastric adenocarcinoma (Autosomal dominant inheritance) Affected status: no Allele origin: germline	European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto Study: ERN GENTURIS Accession: SCV003926967.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Publications: PubMed (1) PubMed: 36436516 Comment: BS2_Supporting (PMID: 30311375) Geographic origin: Europe Comment on evidence: 1 family not fulfilling 2020 HDGC criteria-Familial history of breast cancer
Uncertain significance (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002760869.3 First in ClinVar: Dec 17, 2022 Last updated: Aug 18, 2023
Uncertain significance (Aug 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004215663.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023

Comment:

This missense variant replaces glutamic acid with lysine at codon 864 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with diffuse gastric cancer or lobular breast cancer in the literature, but has been observed in an individual suspected of Lynch syndrome (PMID 25980754), an individual with colorectal cancer (PMID 27978560), an individual affected with ovarian cancer (PMID 30306255), and an individual with a personal and/or family history of breast and/or ovarian cancer (PMID: 29470806). This variant has been identified in 4/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 864 of the CDH1 protein (p.Glu864Lys). This variant is present in population databases (rs142927667, gnomAD 0.006%). This missense change has been observed in individual(s) with various forms of cancer including: colorectal cancer, ovarian cancer, endometrial cancer, breast cancer, giloblastoma, osteosarcoma, and/or clinical features of Lynch syndrome (PMID: 25980754, 27978560, 29470806, 30306255, 34326862, 36271359). ClinVar contains an entry for this variant (Variation ID: 234912). 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.

Comment:

The p.E864K variant (also known as c.2590G>A), located in coding exon 16 of the CDH1 gene, results from a G to A substitution at nucleotide position 2590. The glutamic acid at codon 864 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in individuals from multiple cancer cohorts, including colon cancer, and breast and/or ovarian cancer (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471; Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Bonache S et al. J Cancer Res Clin Oncol, 2018 Dec;144:2495-2513; Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with Lynch syndrome-related cancers or breast and/or ovarian cancers (PMID: 30306255, 29470806, 25980754, 27978560, 33471991); This variant is associated with the following publications: (PMID: 25980754, 27978560, 29470806, 30306255, 36271359, 33471991, 15235021, 22850631, 34326862)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes.	Garcia-Pelaez J	The Lancet. Oncology	2023	PMID: 36436516
Individualized combination therapies based on whole-exome sequencing displayed significant clinical benefits in a glioblastoma patient with secondary osteosarcoma: case report and genetic characterization.	Yi GZ	BMC neurology	2022	PMID: 36271359
Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach.	Bhai P	Frontiers in genetics	2021	PMID: 34326862
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings.	Bonache S	Journal of cancer research and clinical oncology	2018	PMID: 30306255
Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations.	Singh J	Breast cancer research and treatment	2018	PMID: 29470806
Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer.	Pearlman R	JAMA oncology	2017	PMID: 27978560
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.	Yurgelun MB	Gastroenterology	2015	PMID: 25980754

Text-mined citations for rs142927667 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_004360.5(CDH1):c.2590G>A (p.Glu864Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs142927667 ...