Submissions for variant NM_004360.5(CDH1):c.377C>T (p.Pro126Leu)

gnomAD frequency: 0.00004  dbSNP: rs746703615

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163916	SCV000214511	likely benign	Hereditary cancer-predisposing syndrome	2021-07-08	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465184	SCV000545406	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-11-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000679573	SCV000618344	uncertain significance	not provided	2021-12-09	criteria provided, single submitter	clinical testing	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)
Color Diagnostics, LLC DBA Color Health	RCV000163916	SCV000689531	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000465184	SCV000786578	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2018-05-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679573	SCV000806667	uncertain significance	not provided	2017-10-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765302	SCV000896557	uncertain significance	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian neoplasm; Malignant tumor of prostate	2018-10-31	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030610	SCV001193544	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679573	SCV001470280	uncertain significance	not provided	2024-02-04	criteria provided, single submitter	clinical testing	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.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000465184	SCV003927030	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2_Supporting (PMID: 30311375)
Myriad Genetics, Inc.	RCV000465184	SCV004020015	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-06	criteria provided, single submitter	clinical testing	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.