ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.892G>A (p.Ala298Thr) (rs142822590)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV000119169 SCV000864623 benign Hereditary diffuse gastric cancer 2018-11-21 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: BS1, BS2.
GeneDx RCV000235152 SCV000149774 likely benign not specified 2018-02-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000119169 SCV000153898 benign Hereditary diffuse gastric cancer 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115865 SCV000183821 benign Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Does not segregate with disease in family study (genes with incomplete penetrance);Other data supporting benign classification;Other strong data supporting benign classification;Subpopulation frequency in support of benign classification
Illumina Clinical Services Laboratory,Illumina RCV000119169 SCV000398556 likely benign Hereditary diffuse gastric cancer 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 Malignant tumor of colon 2015-02-24 criteria provided, single submitter clinical testing
Color Health, Inc 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 cancer 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034709 SCV000888044 benign not provided 2018-01-04 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034709 SCV001150948 uncertain significance not provided 2017-02-01 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000119169 SCV001439186 benign Hereditary diffuse gastric cancer 2020-09-08 criteria provided, single submitter clinical testing
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 cancer 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.

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