ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4913T>C (p.Met1638Thr) (rs201797422)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213972 SCV000275885 uncertain significance Hereditary cancer-predisposing syndrome 2015-05-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Illumina Clinical Services Laboratory,Illumina RCV000348692 SCV000452018 likely benign APC-Associated Polyposis Disorders 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000549046 SCV000647546 uncertain significance Familial adenomatous polyposis 1 2018-10-13 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 1638 of the APC protein (p.Met1638Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs201797422, ExAC 0.01%) but has not been reported in the literature in individuals with an APC-related disease. ClinVar contains an entry for this variant (Variation ID: 231898). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000213972 SCV000681695 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586239 SCV000694063 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing Variant summary: The APC c.4913T>C (p.Met1638Thr) variant involves the alteration of a conserved nucleotide located in the Adenomatous polyposis coli protein repeat region (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 3/121374 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.000116 (1/8654). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this might be a benign polymorphism found primarily in the populations of East Asian origin. However, the allele number is very small. In addition, one other clinical diagnostic laboratory classified this variant as uncertain significance and another one classified it as Likely benign, all without evidence for independent evaluation. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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