In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with colorectal cancer who also carried a pathogenic variant in MSH2 (Ricker 2017); This variant is associated with the following publications: (PMID: 31871109, 28640387)
ClinVar Genomic variation as it relates to human health
NM_004360.5(CDH1):c.377C>T (p.Pro126Leu)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Uncertain significance(9); Likely benign(2)
Uncertain significance(9); Likely benign(2)
11 out of 12 submissions contributed to this classification
Help
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.
12
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004360.5(CDH1):c.377C>T (p.Pro126Leu)
Variation ID: 184629 Accession: VCV000184629.33
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16q22.1 16: 68801883 (GRCh38) [ NCBI UCSC ] 16: 68835786 (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 Apr 17, 2017 Jun 29, 2025 Nov 27, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004360.5:c.377C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004351.1:p.Pro126Leu missense NM_001317184.2:c.377C>T NP_001304113.1:p.Pro126Leu missense NM_001317185.2:c.-1239C>T 5 prime UTR NM_001317186.2:c.-1443C>T 5 prime UTR NC_000016.10:g.68801883C>T NC_000016.9:g.68835786C>T NG_008021.1:g.69592C>T LRG_301:g.69592C>T LRG_301t1:c.377C>T - Protein change
- P126L
- Other names
- -
- Canonical SPDI
- NC_000016.10:68801882:C:T
-
Global minor allele
frequency (GMAF) HelpThe 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) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00004
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
4982 | 5080 | |
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. |
|---|---|---|---|---|
| Conflicting classifications of pathogenicity (2) |
criteria provided, conflicting classifications
|
Dec 5, 2023 | RCV000163916.17 | |
| Conflicting classifications of pathogenicity (4) |
criteria provided, conflicting classifications
|
Nov 27, 2024 | RCV000465184.18 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 4, 2024 | RCV000679573.14 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000765302.5 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
May 1, 2019 | RCV001030610.4 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 7, 2022 | RCV005359450.1 |
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. |
Expand all rows
Collapse all rows
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
(Oct 31, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial cancer of breast
Blepharocheilodontic syndrome 1 Hereditary diffuse gastric adenocarcinoma Ovarian cancer Familial prostate cancer Endometrial carcinoma |
Fulgent Genetics, Fulgent Genetics
Accession: SCV000896557.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Uncertain significance
(May 01, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary breast and ovarian cancer syndrome |
Cancer Genomics Group, Japanese Foundation For Cancer Research
Accession: SCV001193544.2
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Observation: 1
Collection method: research
Allele origin: germline
Affected status: yes
Observation 1
Collection method: research
Allele origin: germline
Affected status: yes
|
|
|
Uncertain significance
(Dec 09, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Not Provided |
GeneDx
Accession: SCV000618344.3
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
show
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with colorectal cancer who also carried a pathogenic variant in MSH2 (Ricker 2017); This variant is associated with the following publications: (PMID: 31871109, 28640387) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Uncertain significance
(Aug 01, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary diffuse gastric adenocarcinoma
(Autosomal dominant inheritance)
|
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: SCV003927030.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
Geographic origin: Europe
Comment on evidence:
1 family not fulfilling 2020 HDGC criteria-Familial history of breast cancer
|
|
|
Uncertain significance
(Mar 06, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary diffuse gastric adenocarcinoma |
Myriad Genetics, Inc.
Accession: SCV004020015.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Likely benign
(Jul 08, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Ambry Genetics
Accession: SCV000214511.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely benign
(Nov 27, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary diffuse gastric adenocarcinoma |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000545406.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 25, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Apr 07, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary diffuse gastric adenocarcinoma
Ovarian cancer
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. |
Department of Pathology and Laboratory Medicine, Sinai Health System
Accession: SCV005916231.1
First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Uncertain significance
(Oct 13, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
PreventionGenetics, part of Exact Sciences
Accession: SCV000806667.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Feb 04, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001470280.3
First in ClinVar: Jan 26, 2021 Last updated: Jan 19, 2025 |
Comment:
show
The CDH1 c.377C>T (p.Pro126Leu) variant has been reported in the published literature in an individual with breast cancer (PMID: 31871109 (2019)), and in another individual with colorectal cancer who also carried a pathogenic variant in the MSH2 gene (PMID: 28640387 (2017)). In a breast cancer association study, this variant was observed in a reportedly healthy individual (PMID: 33471991 (2021), see LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.000098 (3/30610 chromosomes in South Asian 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Uncertain significance
(Dec 05, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Color Diagnostics, LLC DBA Color Health
Accession: SCV000689531.6
First in ClinVar: Feb 19, 2018 Last updated: May 03, 2025 |
Comment:
show
This missense variant replaces proline with leucine at codon 126 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 31871109) and colorectal cancer (PMID: 28640387). In a large breast cancer case-control study, this variant has been reported in 0/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has also been identified in 9/282034 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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Platform type: NGS
|
|
|
Uncertain significance
(May 29, 2018)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Hereditary diffuse gastric adenocarcinoma |
Counsyl
Accession: SCV000786578.3
First in ClinVar: Apr 17, 2017 Last updated: Jun 29, 2025 |
Comment:
show
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
Comment:
Comment:
BS2_Supporting (PMID: 30311375)
Comment:
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.
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.
Comment:
The CDH1 c.377C>T (p.Pro126Leu) variant has been reported in the published literature in an individual with breast cancer (PMID: 31871109 (2019)), and in another individual with colorectal cancer who also carried a pathogenic variant in the MSH2 gene (PMID: 28640387 (2017)). In a breast cancer association study, this variant was observed in a reportedly healthy individual (PMID: 33471991 (2021), see LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.000098 (3/30610 chromosomes in South Asian 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This missense variant replaces proline with leucine at codon 126 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 31871109) and colorectal cancer (PMID: 28640387). In a large breast cancer case-control study, this variant has been reported in 0/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has also been identified in 9/282034 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 submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Citations for germline classification of this variant
Help| 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 |
| Prevalence of Inherited Mutations in Breast Cancer Predisposition Genes among Women in Uganda and Cameroon. | Adedokun B | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2020 | PMID: 31871109 |
| DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer. | Ricker CN | Cancer | 2017 | PMID: 28640387 |
Text-mined citations for rs746703615 ...
HelpThese 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 Jun 29, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.