ClinVar Miner

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

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115865 SCV000183821 likely benign Hereditary cancer-predisposing syndrome 2017-12-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,Other data supporting benign classification,Other strong data supporting benign classification,Does not segregate with disease in family study (genes with incomplete penetrance)
Biesecker Lab/Human Development 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 Medical Center RCV000148457 SCV000190156 uncertain significance Neoplasm of stomach 2014-06-01 no assertion criteria provided research
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414947 SCV000492813 uncertain significance Colon cancer 2015-02-24 criteria provided, single submitter clinical testing
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.
Color RCV000115865 SCV000537418 likely benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
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.
Illumina Clinical Services Laboratory,Illumina RCV000119169 SCV000398556 likely benign Hereditary diffuse gastric cancer 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000235152 SCV000698412 likely benign not specified 2017-11-09 criteria provided, single submitter clinical testing Variant summary: The CDH1 c.892G>A (p.Ala298Thr) variant involves the alteration of a conserved nucleotide that lies within one of the cadherin domains (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant has been identified in several patients with gastric cancer or related cancers without strong evidence for pathogenicity. 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 activition (Mateus_2009). However, cell adhesion and adhesion activation was shown not to be affected via several different assays (Petrova_2016). Multiple clinical diagnostic laboratories/reputable databases have classified this variant with conflicting interpretations, including uncertain significance (3x), likely benign (4x), and benign (1x), with the most recent ClinVar submissions in 2017 being likely benign and benign. This variant was found in 116/252556 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.001332 (41/30782). This frequency is about 47 times the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000283), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. Additionally, the variant frequency is also above the maximal expected allele frequency in other subpopulations (European (non-Finnish)) and has been identified as a homozygous in a cancer-free female over 70 years old (FLOSSIES database), both suggesting a benign impact of the variant. 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), further supporting a benign impact. Taken together, this variant is classified as likely benign.
Invitae RCV000119169 SCV000153898 benign Hereditary diffuse gastric cancer 2017-12-28 criteria provided, single submitter clinical testing
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

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