Submissions for variant NM_004360.5(CDH1):c.1325T>C (p.Leu442Ser)

gnomAD frequency: 0.00001  dbSNP: rs752074266

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213773	SCV000275032	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-28	criteria provided, single submitter	clinical testing	The p.L442S variant (also known as c.1325T>C), located in coding exon 10 of the CDH1 gene, results from a T to C substitution at nucleotide position 1325. The leucine at codon 442 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228858	SCV000288428	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 442 of the CDH1 protein (p.Leu442Ser). This variant is present in population databases (rs752074266, gnomAD 0.009%). This missense change has been observed in individual(s) with cancer (PMID: 31159747, 36436516). ClinVar contains an entry for this variant (Variation ID: 231246). 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.
Color Diagnostics, LLC DBA Color Health	RCV000213773	SCV000689446	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 442 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CDH1-related disorders in the literature. This variant has been identified in 3/251424 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.
GeneKor MSA	RCV000213773	SCV000821968	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985650	SCV001134053	uncertain significance	not provided	2018-09-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000985650	SCV001826822	uncertain significance	not provided	2023-01-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal or family history of breast, ovarian, and/or other cancers (Tsaousis et al., 2019); This variant is associated with the following publications: (PMID: 31159747, 15235021, 22850631)
Sema4, Sema4	RCV000213773	SCV002529056	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-01	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	RCV000228858	SCV003926780	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	Not applicable criteria (PMID: 30311375)
Baylor Genetics	RCV004567554	SCV005060093	uncertain significance	Familial cancer of breast	2024-02-05	criteria provided, single submitter	clinical testing