ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1004G>A (p.Arg335Gln) (rs373364873)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586292 SCV000149741 uncertain significance not provided 2018-10-08 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.1004G>A at the cDNA level, p.Arg335Gln (R335Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). CDH1 Arg335Gln has been reported in at least one individual with colorectal cancer and no history of gastric cancer (Raskin 2017). CDH1 Arg335Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Cadherin 2 extracellular domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CDH1 Arg335Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115832 SCV000185512 likely benign Hereditary cancer-predisposing syndrome 2020-09-11 criteria provided, single submitter clinical testing Other strong data supporting benign classification
Invitae RCV000229894 SCV000288411 uncertain significance Hereditary diffuse gastric cancer 2020-11-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 335 of the CDH1 protein (p.Arg335Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs373364873, ExAC 0.03%). This variant has been observed in an individual with colorectal cancer and in an individual with breast cancer (PMID: 29212164, 30287823). ClinVar contains an entry for this variant (Variation ID: 127905). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000229894 SCV000488287 uncertain significance Hereditary diffuse gastric cancer 2016-02-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115832 SCV000684319 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855585 SCV000698351 uncertain significance not specified 2019-09-06 criteria provided, single submitter clinical testing Variant summary: CDH1 c.1004G>A (p.Arg335Gln) results in a conservative amino acid change located in the Cadherin-like (IPR002126) 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 2.4e-05 in 251236 control chromosomes, predominantly at a frequency of 5.8e-05 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1004G>A has been reported in the literature in individuals affected with gastric cancer (Rosivatz_2002, Fricke_2003), however it was not clear whether the mutation was somatic or germline in origin. In addition, the variant has been observed in an individual with colorectal cancer and no history of gastric cancer (Raskin_2017) and an individual with breast cancer (Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as uncertain significance. However, co-occurrence with another pathogenic variant has been reported (RAD51C c.706-2A>G), providing supporting evidence for a benign role. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics RCV000229894 SCV000839085 uncertain significance Hereditary diffuse gastric cancer 2018-07-02 criteria provided, single submitter clinical testing

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