VCV000234799.27 - ClinVar

NM_004360.5(CDH1):c.337A>G (p.Lys113Glu)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(4); Likely benign(1)

5 out of 5 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004360.5(CDH1):c.337A>G (p.Lys113Glu)

Variation ID: 234799 Accession: VCV000234799.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q22.1 16: 68801843 (GRCh38) [ NCBI UCSC ] 16: 68835746 (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	Feb 25, 2025	Aug 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004360.5:c.337A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004351.1:p.Lys113Glu	missense
NM_001317184.2:c.337A>G	NP_001304113.1:p.Lys113Glu	missense
NM_001317185.2:c.-1279A>G		5 prime UTR
NM_001317186.2:c.-1483A>G		5 prime UTR
NC_000016.10:g.68801843A>G
NC_000016.9:g.68835746A>G
NG_008021.1:g.69552A>G
LRG_301:g.69552A>G
LRG_301t1:c.337A>G

... more HGVS ... less HGVS

Protein change

K113E

Other names

Canonical SPDI

NC_000016.10:68801842:A:G

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA10577534 dbSNP: rs876661106 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	4837	4932

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	Apr 3, 2018	RCV000217135.9
Hereditary diffuse gastric adenocarcinoma	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 12, 2024	RCV000463944.9
Hereditary cancer-predisposing syndrome	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Apr 26, 2024	RCV000572873.10

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 (Apr 03, 2018) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000279836.10 First in ClinVar: May 29, 2016 Last updated: May 29, 2016	Comment: This variant is denoted CDH1 c.337A>G at the cDNA level, p.Lys113Glu (K113E) at the protein level, and results in the change of a Lysine to … (more) This variant is denoted CDH1 c.337A>G at the cDNA level, p.Lys113Glu (K113E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant has been observed in co-occurrence with a pathogenic MSH6 variant, in one individual with endometrial cancer and a diagnosis of Lynch syndrome (Jori 2015). This variant has also been observed in at least one individual with non-syndromic orofacial cleft, with no specific information about cancer history (Vogelaar 2013). CDH1 Lys113Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). CDH1 Lys113Glu is located in the precursor sequence domain Brooks-WIlson 2004). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CDH1 Lys113Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
Uncertain significance (Aug 12, 2024) C Contributing to aggregate classification	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: SCV000545463.7 First in ClinVar: Apr 17, 2017 Last updated: Feb 25, 2025	Publications: PubMed (2) PubMed: 23197654‚ 30661051 Comment: This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 113 of the CDH1 protein … (more) This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 113 of the CDH1 protein (p.Lys113Glu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with non-syndromic orofacial clefts (PMID: 23197654, 30661051). ClinVar contains an entry for this variant (Variation ID: 234799). 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 tolerated. 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 (Aug 01, 2022) C Contributing to aggregate classification	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: SCV003927023.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Publications: PubMed (1) PubMed: 36436516 Comment: PM2; BS2_Supporting (PMID: 30311375) Geographic origin: Europe Comment on evidence: 1 family not fulfilling 2020 HDGC criteria-Familial history of breast cancer
Uncertain significance (Dec 13, 2022) C Contributing to aggregate classification	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: SCV001340256.3 First in ClinVar: Mar 25, 2020 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 23197654‚ 30661051 Comment: This missense variant replaces lysine with glutamic acid at codon 113 of the CDH1 protein. Computational prediction tool suggests that this variant may not impact … (more) This missense variant replaces lysine with glutamic acid at codon 113 of the CDH1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with orofacial cleft (PMID: 23197654, 30661051) and in a patient with endometrial cancer that also harbored a mutation in MSH6 (c.2569_2572del, p.Asp857Phefs*10, PMID: 26517685). This variant has been identified in 1/251152 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)
Likely benign (Apr 26, 2024) C Contributing to aggregate classification	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: SCV000669001.6 First in ClinVar: Jan 01, 2018 Last updated: Aug 11, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)

Comment:

This variant is denoted CDH1 c.337A>G at the cDNA level, p.Lys113Glu (K113E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant has been observed in co-occurrence with a pathogenic MSH6 variant, in one individual with endometrial cancer and a diagnosis of Lynch syndrome (Jori 2015). This variant has also been observed in at least one individual with non-syndromic orofacial cleft, with no specific information about cancer history (Vogelaar 2013). CDH1 Lys113Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). CDH1 Lys113Glu is located in the precursor sequence domain Brooks-WIlson 2004). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CDH1 Lys113Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

Comment:

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 113 of the CDH1 protein (p.Lys113Glu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with non-syndromic orofacial clefts (PMID: 23197654, 30661051). ClinVar contains an entry for this variant (Variation ID: 234799). 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 tolerated. 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:

This missense variant replaces lysine with glutamic acid at codon 113 of the CDH1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with orofacial cleft (PMID: 23197654, 30661051) and in a patient with endometrial cancer that also harbored a mutation in MSH6 (c.2569_2572del, p.Asp857Phefs*10, PMID: 26517685). This variant has been identified in 1/251152 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 alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
Clinical spectrum and pleiotropic nature of CDH1 germline mutations.	Figueiredo J	Journal of medical genetics	2019	PMID: 30661051
Identification of germline mutations in the cancer predisposing gene CDH1 in patients with orofacial clefts.	Vogelaar IP	Human molecular genetics	2013	PMID: 23197654

Text-mined citations for rs876661106 ...

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 Feb 26, 2025

ClinVar Genomic variation as it relates to human health

NM_004360.5(CDH1):c.337A>G (p.Lys113Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs876661106 ...