ClinVar Miner

Submissions for variant NM_000038.5(APC):c.7490C>T (p.Ser2497Leu) (rs141010008)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131590 SCV000186602 benign Hereditary cancer-predisposing syndrome 2015-09-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Does not segregate with disease in family study (genes with incomplete penetrance),Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,In silico models in agreement (benign),General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Color RCV000131590 SCV000910611 benign Hereditary cancer-predisposing syndrome 2016-03-22 criteria provided, single submitter clinical testing
GeneDx RCV000120032 SCV000209549 likely benign not specified 2017-10-04 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ITMI RCV000120032 SCV000084163 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000587624 SCV000694118 benign not provided 2016-03-25 criteria provided, single submitter clinical testing Variant Summary: The c.7490C>T variant involves the alteration of a conserved nucleotide and 3/4 in silico tools predict a neutral outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.033%, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.055%. This frequency exceeds the maximal expected allele frequency for a pathogenic variant in APC (0.006%), suggesting this is a benign polymorphism found primarily in population(s) of European origin. The variant was reported in a family affected by multiple colorectal adenomas and carcinoma, however was absent in two affected members and was present in 3 unaffected members, showing lack of segregation of the variant with disease (Al-Tassan_2002). While one reputable clinical lab has classified the variant as likely benign, others have classified it as a VUS. Considering the relatively high frequency of this variant in the general population as well as the lack of segregation seen in an affected family, this variant has been classified as Benign.
Invitae RCV000122800 SCV000166057 uncertain significance Familial adenomatous polyposis 1 2018-01-26 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 2497 of the APC protein (p.Ser2497Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs141010008, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in a family affected with colorectal cancer, however, it did not segregate with disease (PMID: 11818965). ClinVar contains an entry for this variant (Variation ID: 133522). 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.
Mendelics RCV000122800 SCV000838150 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing

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