Submissions for variant NM_004360.5(CDH1):c.1118C>T (p.Pro373Leu)

gnomAD frequency: 0.00002  dbSNP: rs587782359

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328221	SCV000864622	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-17	reviewed by expert panel	curation	The c.1118C>T (p.Pro373Leu) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
Ambry Genetics	RCV000131314	SCV000186287	likely benign	Hereditary cancer-predisposing syndrome	2021-02-26	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.
Invitae	RCV000231218	SCV000288417	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000481162	SCV000568307	uncertain significance	not provided	2021-10-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate failure to produce compact cellular aggregates and increased invasion (Corso 2007, Mateus 2009); Observed in individuals with a personal or family history of breast, gastric, ovarian or pancreatic cancer (Roviello 2007, Bunnell 2017, Slavin 2017, Lee 2018, Manchana 2019) and in a family with blepharocheilodontic syndrome (Kievit 2018); This variant is associated with the following publications: (PMID: 17126523, 28767289, 28492532, 22225527, 20373070, 22098830, 19725995, 17545690, 24204729, 17434710, 19268661, 28649662, 27582386, 27276934, 29348693, 28580595, 31815095, 22850631, 15235021, 30982232, 30311375)
Color Diagnostics, LLC DBA Color Health	RCV000131314	SCV000903155	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-12	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 373 of the CDH1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have found the variant protein to be defective in suppressing cell motility (partial) and in cell invasion assays (PMID: 17434710, 19268661). This variant has been reported in individuals who have hereditary diffuse gastric cancer (HDGC)-associated disease, however, the majority of carriers do not have HDGC-associated disease (PMID: 17126523, 27276934, 28649662, 30311375). This variant also has been reported in individuals affected with pancreatic cancer and ovarian cancer (PMID: 28767289, 31815095). This variant has been identified in 8/282884 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780090	SCV000917122	uncertain significance	not specified	2017-12-26	criteria provided, single submitter	clinical testing	Variant summary: The CDH1 c.1118C>T (p.Pro373Leu) variant involves the alteration of a conserved nucleotide located in the Cadherin domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 7/277232 control chromosomes at a frequency of 0.0000252, which does not exceed the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000283). This variant has been reported in one patient with gastric cancer and this patient's unaffected brother. It is not found in this patient's daughter, who had ductal breast cancer (Roviello_2006). A subsequent report on the proband gastric tumor by the same authors showed no LOH or other somatic variants while demonstrating somatic CDH1 promoter hypermethylation suggesting a possible mechanism for the inactivation of wild-type E-cadherin allele in this proband. However, as the phase of this variant relative to the promoter hypermethylated allele in the tumor is not known, it cannot be weighted as a conclusive evidence supporting a deleterious role of this variant. This variant has also been reported in patients with BCR-ABL positive ALL, breast cancer, pancreatic ductal adenocarcinoma and lung cancer without strong evidence supporting causality (Zhang_2015, Bunnell_2016, Slavin_2017, Shindo_2017). In vitro functional studies have shown that this variant affects cell adhesion, cell invasion, activation of EGFR, p38 MAPK and Src kinase (Corso_2007, Mateus_2009). However, the extent of correlation of these functional assays with disease physiology is not clear. In addition, one recent study showed that this variant did not significantly affect cell migration (Petrova_2016). Lastly, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Mendelics	RCV000231218	SCV001140141	benign	Hereditary diffuse gastric adenocarcinoma	2023-08-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000780090	SCV002046241	uncertain significance	not specified	2020-09-22	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153426	SCV003843606	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing