Submissions for variant NM_004360.5(CDH1):c.2398C>T (p.Arg800Cys)

gnomAD frequency: 0.00001  dbSNP: rs587782162

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130753	SCV000185644	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-17	criteria provided, single submitter	clinical testing	The p.R800C variant (also known as c.2398C>T), located in coding exon 15 of the CDH1 gene, results from a C to T substitution at nucleotide position 2398. The arginine at codon 800 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in 1/450 patients with colorectal cancer diagnosed under the age of 50 years who underwent multi-gene panel testing (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). This alteration has also been reported in 1/937 consecutive Chinese breast cancer patients who underwent multi-gene panel testing (Li JY et al. Int. J. Cancer, 2019 01;144:281-289). This alteration has also been reported in two breast cancer-only families in a genotype-first study of families with CDH1 variants (Garcia-Pelaez J et al. Lancet Oncol, 2023 Jan;24:91-106). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204619	SCV000260231	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 800 of the CDH1 protein (p.Arg800Cys). This variant is present in population databases (rs587782162, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer and/or colorectal cancer (PMID: 25186627, 27978560, 29752822). ClinVar contains an entry for this variant (Variation ID: 141990). 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 disruptive. 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.
Counsyl	RCV000204619	SCV000784761	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2017-11-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765308	SCV000896563	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
Color Diagnostics, LLC DBA Color Health	RCV000130753	SCV000904072	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 800 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 colorectal cancer (PMID: 27978560) and breast cancer (PMID: 25186627, 29752822). This variant has also been reported in unaffected individuals with a family history of breast cancer (PMID: 36436516). This variant has also been identified in 2/251410 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.
GeneDx	RCV001544684	SCV001763859	uncertain significance	not provided	2024-07-02	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 personal and/or family history of breast or colorectal cancer (PMID: 25186627, 28944238, 27978560, 29752822, 36436516); This variant is associated with the following publications: (PMID: 27978560, 28944238, 29752822, 25186627, 36436516, 15235021, 22850631)
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000204619	SCV003926935	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PM2; BS2_Supporting (PMID: 30311375)
Myriad Genetics, Inc.	RCV000204619	SCV004019597	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.
Baylor Genetics	RCV003461999	SCV004215706	uncertain significance	Familial cancer of breast	2024-02-13	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000204619	SCV001749934	not provided	Hereditary diffuse gastric adenocarcinoma		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 02-14-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004739447	SCV005346821	uncertain significance	CDH1-related disorder	2024-07-22	no assertion criteria provided	clinical testing	The CDH1 c.2398C>T variant is predicted to result in the amino acid substitution p.Arg800Cys. This variant was reported in individuals with colorectal cancer and breast cancer and in individuals with family history of breast cancer (Pearlman et al. 2017. PubMed ID: 27978560; Li et al. 2018. PubMed ID: 29752822; Garcia-Pelaez et al. 2023. PubMed ID: 36436516). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is classified as variant of uncertain significance in ClinVar. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.