Submissions for variant NM_004360.5(CDH1):c.719A>G (p.Asn240Ser)

dbSNP: rs587780788

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123254	SCV000166561	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 240 of the CDH1 protein (p.Asn240Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 36436516). ClinVar contains an entry for this variant (Variation ID: 136069). 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 tolerated. 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	RCV000767163	SCV000566368	uncertain significance	not provided	2015-04-24	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.719A>G at the cDNA level, p.Asn240Ser (N240S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDH1 Asn240Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. CDH1 Asn240Ser occurs at a position that is not conserved across species and is located in the Cadherin 1 domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether CDH1 Asn240Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486588	SCV000600997	uncertain significance	not specified	2017-01-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575157	SCV000661620	likely benign	Hereditary cancer-predisposing syndrome	2022-11-16	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.
Counsyl	RCV000123254	SCV000785674	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2017-10-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000575157	SCV000908724	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-15	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 240 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 not been identified 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	RCV000486588	SCV001339073	uncertain significance	not specified	2020-03-20	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.719A>G (p.Asn240Ser) results in a conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251458 control chromosomes (gnomAD). 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.719A>G in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six 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.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000123254	SCV003926684	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PM2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000123254	SCV004019604	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.
PreventionGenetics, part of Exact Sciences	RCV003398742	SCV004118958	uncertain significance	CDH1-related disorder	2023-09-29	criteria provided, single submitter	clinical testing	The CDH1 c.719A>G variant is predicted to result in the amino acid substitution p.Asn240Ser. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant has been interpreted as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/136069/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.