ClinVar Miner

Submissions for variant NM_000038.6(APC):c.757G>A (p.Gly253Ser) (rs772806807)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229496 SCV000282827 uncertain significance Familial adenomatous polyposis 1 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 253 of the APC protein (p.Gly253Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs772806807, ExAC 0.01%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 236647). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Ambry Genetics RCV000562662 SCV000667227 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-07 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000229496 SCV000785247 uncertain significance Familial adenomatous polyposis 1 2017-06-19 criteria provided, single submitter clinical testing
Mendelics RCV000229496 SCV000838068 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000562662 SCV000902854 benign Hereditary cancer-predisposing syndrome 2016-06-15 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001156936 SCV001318476 uncertain significance APC-Associated Polyposis Disorders 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Integrated Genetics/Laboratory Corporation of America RCV001193538 SCV001362437 uncertain significance not specified 2019-01-25 criteria provided, single submitter clinical testing Variant summary: APC c.757G>A (p.Gly253Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 276640 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.757G>A has been reported in the literature in cancer samples and individuals affected with cancer, specifically T cell acute lymphoblastic leukemia, familial gastrointestinal polyposis/cancers and pancreatic ductal adenocarcinoma (Kohda_2016, Ohmoto_2016, Kalender_2012). 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. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
3DMed Clinical Laboratory Inc RCV000677749 SCV000803905 uncertain significance Colon cancer 2017-06-14 no assertion criteria provided clinical testing

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