ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6958C>T (p.Pro2320Ser) (rs587778036)

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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 RCV000568801 SCV000667320 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000120029 SCV000694105 uncertain significance not specified 2019-11-01 criteria provided, single submitter clinical testing Variant summary: APC c.6958C>T (p.Pro2320Ser) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) of the encoded protein sequence. 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 4e-06 in 250878 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6958C>T has been reported in the literature in individuals with a personal- and/or family history of breast and ovarian cancer (Cock-Rada_2017, Bonache_2018). These reports 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color RCV000568801 SCV000905994 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-31 criteria provided, single submitter clinical testing
Invitae RCV000818914 SCV000959552 uncertain significance Familial adenomatous polyposis 1 2019-09-03 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 2320 of the APC protein (p.Pro2320Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs587778036, ExAC 0.009%) but has not been reported in the literature in individuals with a APC-related disease. ClinVar contains an entry for this variant (Variation ID: 133521). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on 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.
ITMI RCV000120029 SCV000084160 not provided not specified 2013-09-19 no assertion provided reference population

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