ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.164T>G (p.Val55Gly) (rs587778174)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000119234 SCV000153979 uncertain significance Hereditary diffuse gastric cancer 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 55 of the CDH1 protein (p.Val55Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is present in population databases (rs587778174, ExAC 0.003%). This variant has been reported in the literature in individual(s) affected with breast cancer (PMID: 24969172) and colorectal cancer (PMID: 28135145, 28944238). ClinVar contains an entry for this variant (Variation ID: 132769). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
Ambry Genetics RCV000131233 SCV000186188 likely benign Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);RNA Studies
GeneDx RCV000656817 SCV000321508 uncertain significance not provided 2018-08-16 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.164T>G at the cDNA level, p.Val55Gly (V55G) at the protein level, and results in the change of a Valine to a Glycine (GTG>GGG). This variant has been observed in at least one individual with breast cancer and two with colon cancer (Wen 2014, Yurgelun 2017, DeRycke 2017). CDH1 Val55Gly was also observed in 1/331 healthy Europeans undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. CDH1 Val55Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the precursor sequence domain (Brooks-Wilson 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CDH1 Val55Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000131233 SCV000684372 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-20 criteria provided, single submitter clinical testing This missense variant replaces valine with glycine at codon 55 of the CDH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 24969172), an individual affected with cancer of the cecum (PMID: 28135145) who also has a pathogenic MUTYH covariant, and in unaffected individuals (PMID: 24728327; [FLOSSIES database](https://whi.color.com/variant/16-68835573-T-G)). This variant has been identified in 7/282786 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Counsyl RCV000119234 SCV000785172 uncertain significance Hereditary diffuse gastric cancer 2017-05-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120511 SCV000919114 uncertain significance not specified 2018-10-05 criteria provided, single submitter clinical testing Variant summary: CDH1 c.164T>G (p.Val55Gly) results in a non-conservative amino acid change located in the Cadherin prodomain 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 2.5e-05 in 277140 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.164T>G, has been reported in the literature in individuals affected with colon cancer and recurrent pregnancy loss (Yurgelun_2017, DeRycke_2017, Quintero-Ronderos_2017) . These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer . To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS x4, likely benign x1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656817 SCV001134062 uncertain significance not provided 2020-01-28 criteria provided, single submitter clinical testing
ITMI RCV000120511 SCV000084664 not provided not specified 2013-09-19 no assertion provided reference population

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