ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2440-6C>G (rs139757930)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000417376 SCV000149764 benign not specified 2017-05-01 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.
Invitae RCV000123249 SCV000166555 benign Hereditary diffuse gastric cancer 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115855 SCV000185892 likely benign Hereditary cancer-predisposing syndrome 2015-07-10 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
Illumina Clinical Services Laboratory,Illumina RCV000123249 SCV000398582 likely benign Hereditary diffuse gastric cancer 2016-06-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115855 SCV000684435 likely benign Hereditary cancer-predisposing syndrome 2015-01-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590568 SCV000698385 benign not provided 2016-01-25 criteria provided, single submitter clinical testing Variant summary: Variant affects a non-conserved intronic nucleotide located at a position not widely known to affect splicing. Mutation taster predicts the variant to be neutral along with 5/5 in silico tools via Alamut predicting no significant effect on normal splicing by the variant. The variant was in the large and broad cohorts of the ExAC project at an allele frequency of o,1% which is 63 times higher than the maximal expected allele frequency of a disease causing CDH1 allele (0.0028%) indicating a neutral impact. The variant showed lack of co-segregation with HDGC in one family (Grodecka_GCC_2014) and was shown not to affect splicing and the expression level of the protein (Grodecka_GCC_2014; Molinaro_GCC_2014) further supporting a benign nature. Additionally, clinical diagnostic centers classify variant as Likely Benign/Benign (without evidence to independently evaluate). Considering all evidence, the variant was classified as Benign.
PreventionGenetics,PreventionGenetics RCV000417376 SCV000806661 benign not specified 2016-11-22 criteria provided, single submitter clinical testing
Mendelics RCV000123249 SCV000839099 likely benign Hereditary diffuse gastric cancer 2018-07-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000590568 SCV001150959 likely benign not provided 2017-04-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285145 SCV001471512 likely benign none provided 2020-04-03 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000417376 SCV000691831 benign not specified no assertion criteria provided clinical testing
True Health Diagnostics RCV000115855 SCV000787983 benign Hereditary cancer-predisposing syndrome 2017-11-15 no assertion criteria provided clinical testing
King Laboratory,University of Washington RCV000417376 SCV001251332 benign not specified 2019-09-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357289 SCV001552715 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The CDH1 c.2440-6C>G variant was identified in 3 of 462 proband chromosomes (frequency: 0.006) from individuals or families with diffuse gastric and lung cancer (Guilford 2007, More 2007, Yorczyk 2015). The variant was also identified in the following databases: dbSNP (ID: rs139757930) as With Likely benign, ClinVar (classified as benign by Invitae, as likely benign by GeneDx and Ambry Genetics), Clinvitae (classified as likely benign by ClinVar, Invitae), Insight Colon Cancer Gene Variant Database (1X), and the Zhejiang Colon Cancer Database. The variant was identified in control databases in 453 (1 homozygous) of 277200 chromosomes at a frequency of 0.0016 in the following populations: European in 215 of 126702 chromosomes (freq. 0.002), Latino in 126 of 34420 chromosomes (freq. 0.004), Ashkenazi Jewish in 73 of 10152 chromosomes (freq. 0.007), Other in 29 of 6466 chromosomes (freq. 0.004), South Asian in 6 of 30782 chromosomes (freq.0.0002), African in 4 of 24024 chromosomes (freq. 0.0002), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The c.2440-6C>G variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. There is conflicting evidence in the literature regarding effect on splicing. The variant causes abnormal RNA transcripts compared to RNA from a healthy unrelated control Individuals in More et al. (2007), while in Grodeck√° (2014) results showed mostly correctly spliced transcripts of both wild type and c.2440-6C>G variants. 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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