Submissions for variant NM_004360.5(CDH1):c.854C>T (p.Thr285Ile)

gnomAD frequency: 0.00007  dbSNP: rs587781634

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129743	SCV000184549	likely benign	Hereditary cancer-predisposing syndrome	2021-12-10	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	RCV000656819	SCV000329226	uncertain significance	not provided	2023-09-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of breast cancer and also in unaffected controls (Dorling et al., 2021; Garcia-Pelaez et al., 2023); This variant is associated with the following publications: (PMID: 34359559, 15235021, 22850631, 33471991, 36436516)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534721	SCV000637859	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129743	SCV000689570	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-13	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 285 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control study, this variant has been reported in 3/60463 cases and 2/53459 controls (PMID: 33471991). It has also been reported in an individual with a family history of breast cancer (PMID: 36436516). This variant has been identified in 2/251460 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656819	SCV000888040	uncertain significance	not provided	2024-05-07	criteria provided, single submitter	clinical testing	The CDH1 c.854C>T (p.Thr285Ile) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMID: 34359559 (2021), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CDH1)) as well as reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CDH1)). This variant has been identified in an individual with family history of breast cancer (PMID: 36436516 (2023)). The frequency of this variant in the general population, 0.000008 (2/251460 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics	RCV000534721	SCV001140137	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129743	SCV002529217	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-11	criteria provided, single submitter	curation
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000534721	SCV003926697	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PM2 (PMID: 30311375)
Baylor Genetics	RCV003460901	SCV004215611	uncertain significance	Familial cancer of breast	2023-12-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000534721	SCV005404431	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-09-16	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant been observed in trans with a known pathogenic variant in one or more individuals. Compound heterozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality.
PreventionGenetics, part of Exact Sciences	RCV003925275	SCV004738438	uncertain significance	CDH1-related disorder	2023-11-14	no assertion criteria provided	clinical testing	The CDH1 c.854C>T variant is predicted to result in the amino acid substitution p.Thr285Ile. This variant has been reported in a clinical hereditary cancer genetic testing cohort and in an individual with a family history of breast cancer (Table S3, Lesueur et al. 2021. PubMed ID: 34359559; Supplement, Garcia-Pelaez et al. 2023. PubMed ID: 36436516). This variant is reported in 2 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/16-68845608-C-T?dataset=gnomad_r2_1). It is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141288/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.