Submissions for variant NM_004360.5(CDH1):c.1214A>G (p.Asn405Ser)

gnomAD frequency: 0.00001  dbSNP: rs587778175

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129759	SCV000184566	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.
GeneDx	RCV000656821	SCV000210909	uncertain significance	not provided	2020-09-22	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been observed in individuals with CDH1-related cancers (Bodian 2014, Yurgelun 2017, Hakkaart 2018); This variant is associated with the following publications: (PMID: 28135145, 24728327, 25428177, 29589180)
Invitae	RCV000198487	SCV000254805	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129759	SCV000684339	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-07	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 405 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145) and in healthy control individuals (PMID: 24728327, 29589180). This variant has been identified in 7/251488 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	RCV000120513	SCV000917129	uncertain significance	not specified	2018-03-12	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1214A>G (p.Asn405Ser) results in a conservative amino acid change located in the 3rd Cadherin domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 247626 control chromosomes. The observed variant frequency is approximately 1.14 fold above the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), suggesting the variant may be benign. The c.1214A>G variant has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer, however these reports do not provide unequivocal conclusions about an association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656821	SCV001469479	uncertain significance	not provided	2021-04-13	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000656821	SCV002009866	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
ITMI	RCV000120513	SCV000084666	not provided	not specified	2013-09-19	no assertion provided	reference population