ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1680G>C (p.Thr560=) (rs35741240)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000174098 SCV000167595 benign not specified 2013-12-13 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000132171 SCV000187250 benign Hereditary cancer-predisposing syndrome 2014-08-15 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000174098 SCV000225338 benign not specified 2015-06-02 criteria provided, single submitter clinical testing
Invitae RCV000203779 SCV000262425 benign Hereditary diffuse gastric cancer 2020-12-06 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000203779 SCV000398566 benign Hereditary diffuse gastric cancer 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755230 SCV000602949 benign none provided 2020-02-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132171 SCV000684373 likely benign Hereditary cancer-predisposing syndrome 2015-04-07 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000203779 SCV000788243 likely benign Hereditary diffuse gastric cancer 2018-01-04 criteria provided, single submitter clinical testing CDH1 p.T560T (NM_004360.3:c.1680G>C) has been reported at a frequency of approximately 1 in 100 individuals of European ancestry (exac.broadinstitute.org). This variant frequency is too high to be consistent with the cancer risk syndrome seen with pathogenic CDH1 variants (Hansford 2015). This evidence supports classification of this variant as likely benign. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded.
PreventionGenetics,PreventionGenetics RCV000174098 SCV000806640 benign not specified 2017-01-06 criteria provided, single submitter clinical testing
Mendelics RCV000203779 SCV001140146 benign Hereditary diffuse gastric cancer 2019-05-28 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000174098 SCV000691822 benign not specified no assertion criteria provided clinical testing
True Health Diagnostics RCV000132171 SCV000805256 likely benign Hereditary cancer-predisposing syndrome 2018-04-26 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356388 SCV001551540 likely benign not provided no assertion criteria provided clinical testing The CDH1 p.Thr560= variant was identified in the literature in 1 of 20 normal chromosomes (frequency: 0.025); however the frequency of this variant in an affected population was not provided (Berx 1997). The variant was also identified in dbSNP (ID: rs35741240) as “With Likely benign, other allele”, in the ClinVar database as benign by GeneDx, Ambry Genetics, EGL Genetic Diagnostics, Invitae, ARUP Laboratories and as likely benign by Illumina Clinical Services; in the Clinvitae database as benign by EmyClass; and in the Cosmic and in Zhejiang Colon Cancer Databases 1X in haemangioblastoma. The variant was not identified in MutDB or the Insight Colon Cancer Gene Variant databases. The variant was further identified in the 1000 Genomes Project in 9 of 5000 chromosomes (frequency: 0.002) and in the NHLBI GO Exome Sequencing Project in 25 of 8600 European American and 3 in 4396 in African American alleles. The variant was identified in control databases in 925 of 277220 chromosomes (4 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 19 of 24022 chromosomes (freq: 0.0008), other in 14 of 6464 chromosomes (freq: 0.002), Latino in 46 of 34420 chromosomes (freq: 0.001), European Non-Finnish in 573 of 126722 chromosomes (freq: 0.004), Ashkenazi Jewish in 8 of 10152 chromosomes (freq: 0.0008), East Asian in 2 of 18868 chromosomes (freq: 0.0001), European Finnish in 52 of 25794 chromosomes (freq: 0.002), and South Asian in 211 of 30778 chromosomes (freq: 0.007). The p.Thr560= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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