Submissions for variant NM_004360.5(CDH1):c.1351A>C (p.Ile451Leu)

gnomAD frequency: 0.00001  dbSNP: rs377416092

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132204	SCV000187286	likely benign	Hereditary cancer-predisposing syndrome	2021-11-18	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000586976	SCV000210913	uncertain significance	not provided	2022-06-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15235021, 22850631)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475311	SCV000545416	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 451 of the CDH1 protein (p.Ile451Leu). This variant is present in population databases (rs377416092, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer and/or colorectal cancer (PMID: 25186627, 34250417). ClinVar contains an entry for this variant (Variation ID: 142788). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818330	SCV000698360	uncertain significance	not specified	2023-08-31	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1351A>C (p.Ile451Leu) results in a conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251472 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1351A>C has been reported in the literature in individuals affected with Breast Cancer (e.g. Tung_2015, Dorling_2021) and Colorectal Cancer (Pearlman_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34250417, 25186627, 33471991). Six ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000132204	SCV000903558	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 451 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, but was also reported in healthy control individuals in a breast cancer case-control study (PMID: 25186627, 33471991). This variant has been identified in 4/282886 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.
Genetic Services Laboratory, University of Chicago	RCV001818330	SCV002064839	uncertain significance	not specified	2021-10-11	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000475311	SCV002525991	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-01-27	criteria provided, single submitter	clinical testing	The CDH1 c.1351A>C (p.Ile451Leu) missense change has a maximum subpopulation frequency of 0.022% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-41244246-C-T ). This variant has been reported in one female individual with breast cancer (PMID: 25186627). To our knowledge, this variant has not been reported in individuals with hereditary diffuse gastric cancer. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria, as specified by the CDH1 Variant Curation Expert Panel (PMID: 30311375): no criteria met.
Baylor Genetics	RCV003462038	SCV004215658	uncertain significance	Familial cancer of breast	2024-03-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586976	SCV005624145	uncertain significance	not provided	2023-11-10	criteria provided, single submitter	clinical testing	The CDH1 c.1351A>C (p.Ile451Leu) variant has been reported in the published literature in individuals with colorectal cancer (PMID: 34250417 (2021)) and early-onset breast cancer (PMID: 25186627 (2015)). In a large breast cancer association study, the variant was reported both in healthy individuals and individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CDH1)). The frequency of this variant in the general population, 0.000031 (4/129184 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.