ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1019C>T (p.Thr340Met) (rs61747631)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129966 SCV000184790 likely benign Hereditary cancer-predisposing syndrome 2018-06-19 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence;Other strong data supporting benign classification
Invitae RCV000200215 SCV000254803 uncertain significance Hereditary diffuse gastric cancer 2020-08-22 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 340 of the CDH1 protein (p.Thr340Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs61747631, ExAC 0.02%). This variant has not been reported in the literature in individuals with CDH1-related disease. ClinVar contains an entry for this variant (Variation ID: 141450). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
GeneDx RCV000219875 SCV000278912 uncertain significance not provided 2018-10-30 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.1019C>T at the cDNA level, p.Thr340Met (T340M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has not, to our knowledge, been published in the literature as a germline pathogenic or benign variant. CDH1 Thr340Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDH1 Thr340Met is located in cadherin 2 of the extracellular domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CDH1 Thr340Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000129966 SCV000689428 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-24 criteria provided, single submitter clinical testing
Counsyl RCV000200215 SCV000785199 uncertain significance Hereditary diffuse gastric cancer 2017-06-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781210 SCV000919101 uncertain significance not specified 2017-12-26 criteria provided, single submitter clinical testing Variant summary: The CDH1 c.1019C>T (p.Thr340Met) variant involves the alteration of a non-conserved nucleotide that is located within the cadherin 2 domain (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/246268 control chromosomes at a frequency of 0.0000122, which does not exceed the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000283). The variant has been reported in the literature without strong evidence for or against pathogenicity, though it has been reported as a somatic mutation in colorectal cancer (Giannakis_2014). Multiple clinical diagnostic laboratories classified this variant as uncertain significance, while one clinical diagnostic laboratory classified this as likely benign. Taken together, this variant is classified as VUS until additional information becomes available.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355225 SCV001550048 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The CDH1 p.Thr340Met variant was not identified in the literature nor was it identified in the MutDB, database. The variant was identified in dbSNP (ID: rs61747631) as "With other allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae, GeneDx, Color Genomics, Counsyl), Cosmic (3x in biliary tract or large intestine), and in Zhejiang University databases. The variant was identified in control databases in 3 of 246268 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African in 2 of 15304 chromosomes (freq: 0.0001), European in 1 of 22300 chromosomes (freq: 0.00005), while the variant was not observed in the Other, Latino, European, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Thr340 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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.