Submissions for variant NM_004360.5(CDH1):c.203A>G (p.Tyr68Cys)

gnomAD frequency: 0.00001  dbSNP: rs1284989530

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001014165	SCV001174845	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	The p.Y68C variant (also known as c.203A>G), located in coding exon 3 of the CDH1 gene, results from an A to G substitution at nucleotide position 203. The tyrosine at codon 68 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was identified in 1 of 831 breast cancer cases and 0 of 839 controls within a Chinese cohort (Zeng C et al. Breast Cancer Res Treat, 2020 Jun;181:465-473). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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	RCV001216703	SCV001388513	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-07-19	criteria provided, single submitter	clinical testing	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"; Align-GVGD: "Class C0"). 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. ClinVar contains an entry for this variant (Variation ID: 820574). This missense change has been observed in individual(s) with breast cancer (PMID: 32318955). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 68 of the CDH1 protein (p.Tyr68Cys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001732013	SCV001983581	uncertain significance	not specified	2021-09-27	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.203A>G (p.Tyr68Cys) results in a non-conservative amino acid change located in the Cadherin prodomain (IPR014868) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251446 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.203A>G has been reported in the literature in settings of multigene panel testing in at-least one individual affected with invasive Breast Cancer (example, Zeng_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Lobular Breast or Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001766836	SCV002008013	uncertain significance	not provided	2021-04-09	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); 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 including breast cancer (Zeng 2020); This variant is associated with the following publications: (PMID: 32318955)
Baylor Genetics	RCV003461337	SCV004215657	uncertain significance	Familial cancer of breast	2023-08-28	criteria provided, single submitter	clinical testing