Submissions for variant NM_004360.5(CDH1):c.1501G>A (p.Val501Met)

gnomAD frequency: 0.00004  dbSNP: rs368690400

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131439	SCV000186421	likely benign	Hereditary cancer-predisposing syndrome	2021-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000167909	SCV000218557	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 501 of the CDH1 protein (p.Val501Met). This variant is present in population databases (rs368690400, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and/or gastric cancer (PMID: 34326862, 36436516). ClinVar contains an entry for this variant (Variation ID: 142357). 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.
GeneDx	RCV000585007	SCV000564837	uncertain significance	not provided	2022-07-28	criteria provided, single submitter	clinical testing	Has not been previously published as a pathogenic or benign germline variant to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27904775, 15235021, 22850631, 32175104, 30287823)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000585007	SCV000600960	uncertain significance	not provided	2021-06-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000585007	SCV000692863	uncertain significance	not provided	2017-07-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000167909	SCV000784964	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2017-02-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131439	SCV000903471	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-15	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 501 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 hereditary cancer in the literature. This variant has been identified in 7/282876 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000478959	SCV000917117	uncertain significance	not specified	2022-04-05	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1501G>A (p.Val501Met) results in a conservative amino acid change located in the Cadherin domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251476 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1501G>A in individuals affected with Hereditary Diffuse Gastric Cancer has been reported. Eight 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.
Genetic Services Laboratory, University of Chicago	RCV000478959	SCV002071368	uncertain significance	not specified	2019-11-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131439	SCV002529070	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-17	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	RCV000167909	SCV003926806	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PS4_Supporting (PMID: 30311375)
Myriad Genetics, Inc.	RCV000167909	SCV004019997	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.