ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166605 SCV000217409 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-09 criteria provided, single submitter clinical testing The p.N432K variant (also known as c.1296C>G), located in coding exon 9 of the CDH1 gene, results from a C to G substitution at nucleotide position 1296. The asparagine at codon 432 is replaced by lysine, an amino acid with similar properties. This variant has been reported in a diffuse gastric cancer patient; RNA analysis of gastric tissue obtained from this patient revealed that the this variant could generate a shortened transcript lacking exon 9, which was predicted to result in an in-frame deletion of 183 amino acids in the extracellular domain (Li X et al. Fam. Cancer 2013 Sep; 12(3):547-54). However, this transcript was not detected in the normal tissue from this individual (Li X et al. Fam. Cancer 2013 Sep; 12(3):547-54). In addition, internal RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). In a study of 99 Chinese breast cancer patients with family histories of cancer, this variant was observed in one patient with invasive ductal carcinoma diagnosed at age 47, who had a family history of two relatives with gastric cancer of unknown histology (Yang X et al. PLoS ONE 2015; 10(4):e0125571). This alteration was not observed in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00018 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000460665 SCV000545471 uncertain significance Hereditary diffuse gastric cancer 2020-06-07 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. 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, 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.
Color Health, Inc RCV000166605 SCV000903557 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193905 SCV001363073 uncertain significance not specified 2019-12-23 criteria provided, single submitter clinical testing Variant summary: CDH1 c.1296C>G (p.Asn432Lys) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/5 computational tools predict no significant impact on normal splicing. However, one experimental study showed this variant generated the exon9-skipping (Li_2013). However, in the absence of experimental evidence evaluating an impact on protein function, this observation does not allow convincing conclusions about the variant effect. Furthermore, the ACMG guidelines for CDH1 variants recommend a supporting (not strong or moderate) weight for evidence that would result in in-frame transcripts such as deletion of exon 9 in CDH1. The variant allele was found at a frequency of 2.9e-05 in 274816 control chromosomes (gnomAD and publications). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1296C>G has been reported in the literature in individuals affected with breast cancer and gastric cancer as well as in two health controls (Li_2013, Yang_2015, Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
3DMed Clinical Laboratory Inc RCV000677870 SCV000804031 likely pathogenic Neoplasm of stomach 2017-12-08 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.