VCV000231246.26 - ClinVar

NM_004360.5(CDH1):c.1325T>C (p.Leu442Ser)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Uncertain significance

9 out of 9 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.1325T>C (p.Leu442Ser)

Variation ID: 231246 Accession: VCV000231246.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q22.1 16: 68815519 (GRCh38) [ NCBI UCSC ] 16: 68849422 (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	Dec 26, 2017	Feb 25, 2025	Dec 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004360.5:c.1325T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004351.1:p.Leu442Ser	missense
NM_001317184.2:c.1142T>C	NP_001304113.1:p.Leu381Ser	missense
NM_001317185.2:c.-224T>C		5 prime UTR
NM_001317186.2:c.-495T>C		5 prime UTR
NC_000016.10:g.68815519T>C
NC_000016.9:g.68849422T>C
NG_008021.1:g.83228T>C
LRG_301:g.83228T>C
LRG_301t1:c.1325T>C

... more HGVS ... less HGVS

Protein change

L442S, L381S

Other names

Canonical SPDI

NC_000016.10:68815518:T:C

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.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA8130071 dbSNP: rs752074266 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.
Hereditary cancer-predisposing syndrome	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	May 28, 2024	RCV000213773.14
Hereditary diffuse gastric adenocarcinoma	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Nov 12, 2024	RCV000228858.13
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 7, 2024	RCV000985650.6
Familial cancer of breast	Uncertain significance (1)	criteria provided, single submitter	Feb 5, 2024	RCV004567554.1

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 28, 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: SCV000275032.8 First in ClinVar: May 29, 2016 Last updated: Aug 11, 2024	Publications: PubMed (1) PubMed: 31159747 Comment: The p.L442S variant (also known as c.1325T>C), located in coding exon 10 of the CDH1 gene, results from a T to C substitution at nucleotide … (more) The p.L442S variant (also known as c.1325T>C), located in coding exon 10 of the CDH1 gene, results from a T to C substitution at nucleotide position 1325. The leucine at codon 442 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. (less)
Uncertain significance (Nov 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: SCV000288428.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 25, 2025	Publications: PubMed (2) PubMed: 31159747‚ 36436516 Comment: This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 442 of the CDH1 protein (p.Leu442Ser). … (more) This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 442 of the CDH1 protein (p.Leu442Ser). This variant is present in population databases (rs752074266, gnomAD 0.009%). This missense change has been observed in individual(s) with cancer (PMID: 31159747, 36436516). ClinVar contains an entry for this variant (Variation ID: 231246). 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 (Aug 01, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	GeneKor MSA Accession: SCV000821968.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018
Uncertain significance (Jan 01, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002529056.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The CDH1 c.1325T>C (p.L442S) variant has been reported in at least one individual with breast cancer, as well as in an individual undergoing hereditary cancer … (more) The CDH1 c.1325T>C (p.L442S) variant has been reported in at least one individual with breast cancer, as well as in an individual undergoing hereditary cancer multi-gene panel testing (PMID: 33471991, 31159747). It was observed in 3/34592 chromosomes of the Latino subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 231246). In silico tools suggest the impact of the variant on protein function is deleterious, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)	Publications: PubMed (2) PubMed: 33471991‚ 31159747
Uncertain significance (Jan 19, 2023) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001826822.2 First in ClinVar: Sep 08, 2021 Last updated: Feb 07, 2023	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal or family history … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal or family history of breast, ovarian, and/or other cancers (Tsaousis et al., 2019); This variant is associated with the following publications: (PMID: 31159747, 15235021, 22850631) (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: SCV003926780.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Publications: PubMed (1) PubMed: 36436516 Comment: Not applicable criteria (PMID: 30311375) Geographic origin: Europe Comment on evidence: 1 family not fulfilling 2020 HDGC criteria-Familial history of breast cancer
Uncertain significance (Nov 16, 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: SCV000689446.5 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Comment: This missense variant replaces leucine with serine at codon 442 of the CDH1 protein. To our knowledge, functional studies have not been reported for this … (more) This missense variant replaces leucine with serine at codon 442 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 CDH1-related disorders in the literature. This variant has been identified in 3/251424 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 (Feb 05, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005060093.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Uncertain significance (Dec 07, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001134053.3 First in ClinVar: Jan 05, 2020 Last updated: Jan 19, 2025	Publications: PubMed (4) PubMed: 36436516‚ 33471991‚ 31159747‚ 31206626 Comment: The CDH1 c.1325T>C (p.Leu442Ser) variant has been reported in the published literature in individuals with a personal and/or family history of breast cancer (PMID: 36436516 … (more) The CDH1 c.1325T>C (p.Leu442Ser) variant has been reported in the published literature in individuals with a personal and/or family history of breast cancer (PMID: 36436516 (2023), 33471991 (2021), 31159747 (2019), see also LOVD (http://databases.lovd.nl/shared)), and in reportedly healthy individuals (PMID: 33471991 (2021), 31206626 (2019), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.000087 (3/34592 chromosomes in Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)

Comment:

The p.L442S variant (also known as c.1325T>C), located in coding exon 10 of the CDH1 gene, results from a T to C substitution at nucleotide position 1325. The leucine at codon 442 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Comment:

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 442 of the CDH1 protein (p.Leu442Ser). This variant is present in population databases (rs752074266, gnomAD 0.009%). This missense change has been observed in individual(s) with cancer (PMID: 31159747, 36436516). ClinVar contains an entry for this variant (Variation ID: 231246). 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:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal or family history of breast, ovarian, and/or other cancers (Tsaousis et al., 2019); This variant is associated with the following publications: (PMID: 31159747, 15235021, 22850631)

Comment:

This missense variant replaces leucine with serine at codon 442 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 CDH1-related disorders in the literature. This variant has been identified in 3/251424 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:

The CDH1 c.1325T>C (p.Leu442Ser) variant has been reported in the published literature in individuals with a personal and/or family history of breast cancer (PMID: 36436516 (2023), 33471991 (2021), 31159747 (2019), see also LOVD (http://databases.lovd.nl/shared)), and in reportedly healthy individuals (PMID: 33471991 (2021), 31206626 (2019), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.000087 (3/34592 chromosomes in Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

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
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
Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer.	Weitzel JN	Cancer	2019	PMID: 31206626
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.	Tsaousis GN	BMC cancer	2019	PMID: 31159747

Text-mined citations for rs752074266 ...

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.1325T>C (p.Leu442Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs752074266 ...