Submissions for variant NM_004360.5(CDH1):c.752C>T (p.Thr251Met)

dbSNP: rs1454205778

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001178778	SCV001343290	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-03	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 251 of the CDH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251464 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001302588	SCV001491802	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-04-13	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 834042). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 251 of the CDH1 protein (p.Thr251Met). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. 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.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV001302588	SCV003926685	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PM2; BS2_Supporting (PMID: 30311375)
Ambry Genetics	RCV001178778	SCV005095376	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-29	criteria provided, single submitter	clinical testing	The p.T251M variant (also known as c.752C>T), located in coding exon 6 of the CDH1 gene, results from a C to T substitution at nucleotide position 752. The threonine at codon 251 is replaced by methionine, an amino acid with similar properties. 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. Based on the available evidence, the clinical significance of this variant remains unclear.
University of Washington Center for Mendelian Genomics, University of Washington	RCV001034592	SCV001197972	likely pathogenic	Cleft lip with or without cleft palate		no assertion criteria provided	research