ClinVar Miner

Submissions for variant NM_000038.6(APC):c.835-3T>C

gnomAD frequency: 0.00002  dbSNP: rs372090940
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164509 SCV000215160 likely benign Hereditary cancer-predisposing syndrome 2019-06-19 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;RNA Studies
Counsyl RCV000409101 SCV000487966 uncertain significance Familial adenomatous polyposis 1 2015-12-22 criteria provided, single submitter clinical testing
GeneDx RCV000432869 SCV000531163 likely benign not specified 2017-09-01 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 RCV002228722 SCV000552752 likely benign Familial adenomatous polyposis 1 2021-12-11 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000164509 SCV000911385 benign Hereditary cancer-predisposing syndrome 2017-04-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000432869 SCV001748700 likely benign not specified 2021-07-04 criteria provided, single submitter clinical testing Variant summary: APC c.835-3T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 250968 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.835-3T>C has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with colorectal cancer (example, Yurgelun_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with a majority consensus leaning towards benign (n=1)/likely benign(n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory,University of Chicago RCV000432869 SCV002071997 uncertain significance not specified 2021-11-19 criteria provided, single submitter clinical testing DNA sequence analysis of the APC gene demonstrated a sequence change in intron 8, c.835-3T>C. This sequence change has been described in the gnomAD database with a frequency of 0.004% in the non-Finnish European subpopulation (dbSNP rs372090940). This sequence change is not predicted to have a deleterious effect on splicing based on in-silico splice prediction programs. This sequence change has been previously described in an individual with colorectal cancer (PMID: 28135145). It is possible that this sequence change represents a benign sequence change in the APC gene that has not been identified to date. The functional significance of this sequence change is not known at present and its contribution to this individual's disease phenotype cannot definitively be determined.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV001729422 SCV001977774 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001729422 SCV001977994 likely benign not provided no assertion criteria provided clinical testing

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