ClinVar Miner

Submissions for variant NM_000038.6(APC):c.531+2T>A (rs863225365)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491613 SCV000579920 pathogenic Hereditary cancer-predisposing syndrome 2019-05-28 criteria provided, single submitter clinical testing The c.531+2T>A intronic pathogenic mutation results from a T to A substitution two nucleotides after coding exon 4 in the APC gene. This alteration has been seen in individuals with a personal and family history consistent with APC-associated disease (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193574 SCV001362489 likely pathogenic Familial multiple polyposis syndrome 2019-12-31 criteria provided, single submitter clinical testing Variant summary: APC c.531+2T>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing:4 predict that the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 232438 control chromosomes (gnomAD). c.531+2T>A has been reported in the literature in at least one individual affected with mild Familial Adenomatous Polyposis (Wang_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001203374 SCV001374536 pathogenic Familial adenomatous polyposis 1 2020-08-06 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the APC gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 12010888, 15459959, 22987206, 17411426, 20977806, 31113927, 20924072). ClinVar contains an entry for this variant (Variation ID: 217994). Experimental studies have shown that disruption of this splice site affects mRNA splicing (PMID: 15459959). ClinVar contains an entry for this variant (Variation ID: 217994). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000202121 SCV000257013 likely pathogenic not provided no assertion criteria provided research

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