Submissions for variant NM_004360.5(CDH1):c.2595G>C (p.Trp865Cys)

gnomAD frequency: 0.00002  dbSNP: rs778019174

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197400	SCV000254827	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-07-16	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 865 of the CDH1 protein (p.Trp865Cys). This variant is present in population databases (rs778019174, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 216595). 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.
Ambry Genetics	RCV000572174	SCV000666310	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	The p.W865C variant (also known as c.2595G>C), located in coding exon 16 of the CDH1 gene, results from a G to C substitution at nucleotide position 2595. The tryptophan at codon 865 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified via multi-gene panel testing for hereditary cancer risk assessment in a Turkish colorectal cancer cohort and a Chinese breast and/or ovarian cancer cohort (Erdem HB et al. Turk J Med Sci, 2020 06;50:1015-1021; Shao D et al. Cancer Sci, 2020 Feb;111:647-657). In another study, this alteration was not seen in 732 breast cancer patients or 189 colorectal cancer patients but detected in 1/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This alteration was also detected in 1/195 individuals with breast cancer, however, this individual was also found to carry two missense alterations in the BRCA2 gene (Subaolu A et al. Eur J Breast Health, 2023 Jan;19:55-69). 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.
Color Diagnostics, LLC DBA Color Health	RCV000572174	SCV000689521	uncertain significance	Hereditary cancer-predisposing syndrome	2018-11-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765310	SCV000896565	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
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000572174	SCV003936138	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-05	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 865 of the CDH1 protein (p.Trp865Cys).This amino acid position is highly conserved (PhyloP=9.71) . This variant is present in population databases (rs778019174, gnomAD 0.006%). This alteration has been identified via multi-gene panel testing for hereditary cancer risk assessment in a Turkish colorectal cancer cohort and a Chinese breast and/or ovarian cancer cohort (Erdem HB et al. Turk J Med Sci, 2020 06;50:1015-1021; Shao D et al. Cancer Sci, 2020 Feb;111:647-657).. ClinVar contains an entry for this variant (Variation ID: 216595). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"). 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. Heterozygous variants in the CDH1 gene cause increased
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315418	SCV004015263	uncertain significance	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 865 of the CDH1 protein (p.Trp865Cys).This amino acid position is highly conserved (PhyloP=9.71) . This variant is present in population databases (rs778019174, gnomAD 0.006%). This alteration has been identified via multi-gene panel testing for hereditary cancer risk assessment in a Turkish colorectal cancer cohort and a Chinese breast and/or ovarian cancer cohort (Erdem HB et al. Turk J Med Sci, 2020 06;50:1015-1021; Shao D et al. Cancer Sci, 2020 Feb;111:647-657).. ClinVar contains an entry for this variant (Variation ID: 216595). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493490	SCV004242736	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing