Submissions for variant NM_004360.5(CDH1):c.892G>A (p.Ala298Thr)

gnomAD frequency: 0.00028  dbSNP: rs142822590

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328163	SCV000864623	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-10	reviewed by expert panel	curation	The c.892G>A (p.Ala298Thr) variant has an allele frequency of 0.00133 (0.1%, 41/30,782 alleles) in the South Asian subpopulation of the gnomAD cohort (BS1). This variant has also been observed in >10 without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS1, BS2.
GeneDx	RCV000034709	SCV000149774	likely benign	not provided	2020-10-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20373070, 16501831, 20233471, 22098830, 26072394, 17545690, 27153395, 29295527, 30212499, 19268661, 24373500, 24204729, 15235021, 22703879, 25637381, 22470475, 16924464, 25980754, 16527687, 24690483, 27582386, 28767289, 30311375, 29522266, 28873162)
Invitae	RCV000119169	SCV000153898	benign	Hereditary diffuse gastric adenocarcinoma	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115865	SCV000183821	benign	Hereditary cancer-predisposing syndrome	2019-01-17	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Illumina Laboratory Services, Illumina	RCV000119169	SCV000398556	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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414947	SCV000492813	uncertain significance	Colon cancer	2015-02-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115865	SCV000537418	likely benign	Hereditary cancer-predisposing syndrome	2015-12-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235152	SCV000698412	benign	not specified	2021-04-01	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.892G>A (p.Ala298Thr) results in a non-conservative amino acid change located in the Cadherin-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 252614 control chromosomes, predominantly at a frequency of 0.0014 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 49-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 South Asian origin. Additionally, the variant frequency is also above the estimated maximal expected allele frequency for a pathogenic variant in other subpopulations (European (non-Finnish)) and has been identified in a homozygous female over 70 years old who has never had cancer (FLOSSIES database), while it was also detected in 435 cases either reported unaffected or having non-CDH1 tumors (Lee_2018). Also, the variant has been found to co-occur with likely pathogenic or pathogenic mutations in at least 2 affected patients (TP53 c.673-1G>A; MLH1 p.Val479Ilefs*6) (Heitzer_2013, Yurgelun_2015), further supporting a benign impact. The variant has been identified in several patients with gastric cancer or related cancers without strong evidence for pathogenicity (e.g. Brooks-Wilson_2004, Garziera_2013, Hansford_2015, Caggiari_2018). One family study found the variant in a 32 year old patient with mixed-type gastric cancer, but also found the variant in two first-degree relatives who were cancer-free, one of whom was 71 years old (van der Post_2015). A functional study has shown that the variant causes increased cellular motility and EGFR activation (Mateus_2009). However, cell adhesion and adhesion activation was shown not to be affected via several different assays (Petrova_2016). Important to note, the variant curation expert panel (VCEP) for CDH1 gene convened by The ClinGen Hereditary Cancer Clinical Domain Working Group commented that functional assays for missense alterations should not be used for CDH1 variant classification (Lee_2018). Nine ClinVar submitters including an expert panel (ClinGen CDH1 Variant Curation Expert Panel) (evaluation after 2014) cite the variant as benign/likely benign and two ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000119169	SCV000839082	likely benign	Hereditary diffuse gastric adenocarcinoma	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235152	SCV000888044	benign	not specified	2022-03-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034709	SCV001150948	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	CDH1: BP4, BS1
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000119169	SCV001439186	benign	Hereditary diffuse gastric adenocarcinoma	2020-09-08	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798069	SCV002043281	likely benign	Breast and/or ovarian cancer	2023-03-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034709	SCV002048286	benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115865	SCV002529221	benign	Hereditary cancer-predisposing syndrome	2021-03-24	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000235152	SCV002551760	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	RCV000119169	SCV003926700	benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS1; BS2 (PMID: 30311375)
PreventionGenetics, part of Exact Sciences	RCV003964835	SCV004778020	likely benign	CDH1-related disorder	2022-04-28	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034709	SCV000043244	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
CSER _CC_NCGL, University of Washington	RCV000148457	SCV000190156	uncertain significance	Neoplasm of stomach	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000119169	SCV001549669	likely benign	Hereditary diffuse gastric adenocarcinoma		no assertion criteria provided	clinical testing	The CDH1 p.Ala298Thr variant was identified in 3 of 1228 proband chromosomes (frequency: 0.0024) from individuals or families with gastric cancer families and atherosclerosis phenotypes, but not for personal or family histories of cancer (Brooks-Wilson 2004, Johnston 2013). The variant was also identified in dbSNP (ID: rs142822590) as “With other allele”, in ClinVar (9x as benign by Invitae, likely benign by GeneDx, Ambry Genetics, Illumina, Color Genomics, and uncertain significance by Center for Mendelian Genomics, Integrated Genetics, University of Washington Medical Center, Biesecker Lab), Clinvitae (6x), and Zhejiang University Database (3x). The variant was not identified in the Cosmic, or MutDB databases. The variant was identified in control databases in 114 of 277202 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 3 of 6466 chromosomes (freq: 0.00046), Latino in 3 of 34418 chromosomes (freq: 0.000087), European Non-Finnish in 67 of 126698 chromosomes (freq: 0.00053), and South Asian in 41 of 30782 chromosomes (freq: 0.0013); it was not observed in the African, Ashkenazi Jewish, East Asian, or Finnish populations. This variant was identified by our laboratory in a patient with breast and ovarian cancer with a co-occurring pathogenic variant of the RAD51C gene (c.701C>G, p.Ser234X) in our laboratory, increasing the likelihood that the p.Ala298Thr variant does not have clinical significance. In a functional study cell lines expressing extracellular mutant forms of E-cadherin (T118R, L214P, G239R, A298T and P373L) displayed higher EGFR activation than cells expressing wild-type E-cadherin. Similarly results revealed that cells expressing E-cadherin with mutations within the extracellular domain (L214P, G239R, A298T, T340A and P373L) displayed a 2 to 3 fold increase in motility when compared to wild-type E-cadherin expressing cells; suggesting that these mutations are effecting EGFR activation (Mateus 2009 19268661). One study considered multivariate approach to infer the significance of missense variants of the E-cadherin gene (CDH1); it included co-segregation of the mutation within pedigrees, frequency in healthy population control, recurrence in independent families, and functional in vitro and in silico data. In this study the p.Ala298Thr variant was not identified in control population and no co-segregation and recurrence was observed (Suriano 2006). The p.Ala298 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357769	SCV001553335	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Ala298Thr variant was identified in 3 of 1228 proband chromosomes (frequency: 0.0024) from individuals or families with gastric cancer families and atherosclerosis phenotypes, but not for personal or family histories of cancer (Brooks-Wilson 2004, Johnston 2013). The variant was also identified in dbSNP (ID: rs142822590) as “With other allele”, in ClinVar (9x as benign by Invitae, likely benign by GeneDx, Ambry Genetics, Illumina, Color Genomics, and uncertain significance by Center for Mendelian Genomics, Integrated Genetics, University of Washington Medical Center, Biesecker Lab), Clinvitae (6x), and Zhejiang University Database (3x). The variant was not identified in the Cosmic, or MutDB databases. The variant was identified in control databases in 114 of 277202 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 3 of 6466 chromosomes (freq: 0.00046), Latino in 3 of 34418 chromosomes (freq: 0.000087), European Non-Finnish in 67 of 126698 chromosomes (freq: 0.00053), and South Asian in 41 of 30782 chromosomes (freq: 0.0013); it was not observed in the African, Ashkenazi Jewish, East Asian, or Finnish populations. This variant was identified by our laboratory in a patient with breast and ovarian cancer with a co-occurring pathogenic variant of the RAD51C gene (c.701C>G, p.Ser234X) in our laboratory, increasing the likelihood that the p.Ala298Thr variant does not have clinical significance. In a functional study cell lines expressing extracellular mutant forms of E-cadherin (T118R, L214P, G239R, A298T and P373L) displayed higher EGFR activation than cells expressing wild-type E-cadherin. Similarly results revealed that cells expressing E-cadherin with mutations within the extracellular domain (L214P, G239R, A298T, T340A and P373L) displayed a 2 to 3 fold increase in motility when compared to wild-type E-cadherin expressing cells; suggesting that these mutations are effecting EGFR activation (Mateus 2009 19268661). One study considered multivariate approach to infer the significance of missense variants of the E-cadherin gene (CDH1); it included co-segregation of the mutation within pedigrees, frequency in healthy population control, recurrence in independent families, and functional in vitro and in silico data. In this study the p.Ala298Thr variant was not identified in control population and no co-segregation and recurrence was observed (Suriano 2006). The p.Ala298 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000235152	SCV001809647	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000235152	SCV001954921	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000034709	SCV001980422	likely benign	not provided		no assertion criteria provided	clinical testing