Submissions for variant NM_004360.5(CDH1):c.808T>G (p.Ser270Ala)

gnomAD frequency: 0.00038  dbSNP: rs587776399

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328218	SCV004035096	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-17	reviewed by expert panel	curation	The c.808T>G (p.Ser270Ala) variant has a maximum subpopulation frequency of 0.002269 (0.2269%, 57 of 25124 alleles) in the European (Finnish) subpopulation of the gnomAD v2.1.1 cohort (BA1). This variant has also has been observed in more than 10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000185687.6, SCV000254832.8). In summary, this variant meets criteria to be classified as benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BS2.
Ambry Genetics	RCV000130793	SCV000185687	likely benign	Hereditary cancer-predisposing syndrome	2018-08-22	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	RCV000235151	SCV000210905	likely benign	not provided	2019-05-13	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26182300, 11948460, 19725995, 17545690, 11705864, 22098830, 27582386, 29928469, 30333958, 32426482)
Invitae	RCV000144457	SCV000254832	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000144457	SCV000398554	likely benign	Hereditary diffuse gastric adenocarcinoma	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Counsyl	RCV000144457	SCV000786564	likely benign	Hereditary diffuse gastric adenocarcinoma	2018-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130793	SCV000910717	likely benign	Hereditary cancer-predisposing syndrome	2016-03-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000144457	SCV001140136	benign	Hereditary diffuse gastric adenocarcinoma	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192624	SCV001360874	likely benign	not specified	2019-02-01	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.808T>G (p.Ser270Ala) results in a conservative amino acid change located in the second cadherin repeat (IPR002126) 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 0.00044 in 282828 control chromosomes, predominantly at a frequency of 0.0023 within the Finnish subpopulation in the gnomAD database. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 80 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. c.808T>G has been reported in the literature in individuals affected with gastric cancer and breast/ovary cancer (e.g. Ikonen 2001, Brovkina 2018). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. At least one publication reported experimental evidence evaluating an impact on protein function, demonstarating that the variant resulted in a strong adhesion but a bit lower than that of WT, the effect on cell migration in a wound closure assay was similar to WT, however, the variant protein was not activatable in CHO cells (Petrova 2016). The significance of these results at the cellular level remains however unclear. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (4 classifying it as likely benign, and 1 as a VUS). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235151	SCV002046227	likely benign	not provided	2020-09-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130793	SCV002529211	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-01	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001192624	SCV002760853	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000144457	SCV003926689	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000144457	SCV004019605	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.
Laboratório de Genética Humana e Médica, Universidade Federal do Pará	RCV000144457	SCV000189523	untested	Hereditary diffuse gastric adenocarcinoma		no assertion provided	not provided	Converted during submission to not provided.