ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7402T>C (p.Ser2468Pro) (rs375586273)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163734 SCV000214309 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000760993 SCV000890908 uncertain significance Neuroepithelial neoplasm; malignant granular cell tumor 2016-09-07 no assertion criteria provided clinical testing
Color RCV000163734 SCV000687125 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-03 criteria provided, single submitter clinical testing
Counsyl RCV000234737 SCV000487829 uncertain significance Familial adenomatous polyposis 1 2015-12-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779738 SCV000916509 uncertain significance not specified 2018-09-28 criteria provided, single submitter clinical testing Variant summary: APC c.7402T>C (p.Ser2468Pro) results in a non-conservative amino acid change located in the adenomatous polyposis coli protein basic domain (IPR009234). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 245882 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7402T>C has been reported in the literature in an individual affected with breast cancer (Tung 2014), however this report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Co-occurrence with another pathogenic variant has been reported in a colorectal carcinoma patient (Rohlin 2016: PMS2 c.861_864delACAG, p.Arg287fsX19), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000234737 SCV000282820 uncertain significance Familial adenomatous polyposis 1 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 2468 of the APC protein (p.Ser2468Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. This variant is present in population databases (rs375586273, ExAC 0.004%). This variant has been reported in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 184474). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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