ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4424C>T (p.Ala1475Val) (rs375380414)

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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 RCV000165744 SCV000216487 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
University of Washington Department of Laboratory Medicine,University of Washington RCV000210169 SCV000266142 uncertain significance Colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000530841 SCV000647516 uncertain significance Familial adenomatous polyposis 1 2018-07-03 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1475 of the APC protein (p.Ala1475Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs375380414, ExAC 0.001%). This variant has been reported in an individual affected with polyposis and colon cancer (PMID: 26845104) and in an individual with a personal and/or family history of cancer (PMID: 28717660). ClinVar contains an entry for this variant (Variation ID: 186197). 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 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.
Color RCV000165744 SCV000681665 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-17 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000607446 SCV000731387 uncertain significance not specified 2017-02-25 criteria provided, single submitter clinical testing The p.Ala1475Val variant in APC has been reported in one individual with colorec tal cancer (Shirts 2016) and has also been reported in ClinVar (Variation ID 186 197). This variant has also been identified in 1/66712 of European chromosomes b y the Exome Aggregation Consortium (ExAC,; dbSNP rs375380414). Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. In summary, the cl inical significance of the p.Ala1475Val variant is uncertain.

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