ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1296C>G (p.Asn432Lys) (rs187862045)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3DMed Clinical Laboratory Inc RCV000677870 SCV000804031 likely pathogenic Neoplasm of stomach 2017-12-08 no assertion criteria provided clinical testing
Ambry Genetics RCV000166605 SCV000217409 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000166605 SCV000903557 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-22 criteria provided, single submitter clinical testing
Invitae RCV000460665 SCV000545471 uncertain significance Hereditary diffuse gastric cancer 2016-12-14 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 432 of the CDH1 protein (p.Asn432Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs187862045, ExAC 0.03%). This variant has been reported in individuals affected with gastric cancer (PMID: 23435907) and breast cancer (PMID: 25927356). ClinVar contains an entry for this variant (Variation ID: 186937). An experimental study has shown that an abnormal mRNA transcript, lacking exon 9, was detected in a gastric tumor sample from an individual carrying this variant (PMID: 23425907). However, this transcript was not detected in normal tissues from this individual, suggesting that it could be the result of a somatic change. A second abnormal transcript, 1054del83, was detected in both normal tissue and a gastric tumor samples from this individual, but was also present in both normal control and tumor tissue samples from several other individuals with gastric cancer who did not have a CDH1 variant, suggesting that this is a naturally-occurring transcript. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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