ClinVar Miner

Submissions for variant NM_000038.5(APC):c.7717A>G (p.Ile2573Val) (rs145444830)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163980 SCV000214580 likely benign Hereditary cancer-predisposing syndrome 2017-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance,No disease association in appropriately sized case-control study(ies),Other data supporting benign classification
Biesecker Lab/Human Development Section,National Institutes of Health RCV000034421 SCV000043140 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
CSER_CC_NCGL; University of Washington Medical Center RCV000148373 SCV000190067 uncertain significance Colorectal adenoma 2014-06-01 no assertion criteria provided research
Color RCV000163980 SCV000910847 likely benign Hereditary cancer-predisposing syndrome 2016-06-07 criteria provided, single submitter clinical testing
Counsyl RCV000122803 SCV000489022 uncertain significance Familial adenomatous polyposis 1 2016-08-05 criteria provided, single submitter clinical testing
GeneDx RCV000034421 SCV000292853 uncertain significance not provided 2017-07-20 criteria provided, single submitter clinical testing This variant is denoted APC c.7717A>G at the cDNA level, p.Ile2573Val (I2573V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). Azzopardi et al. (2008) identified this variant in 1/691 individuals with a history of multiple colorectal adenomas and 0/969 control subjects, while Johnston et al. (2012) reported it in 1/571 individuals with atherosclerosis, with no specific information about cancer history. APC Ile2573Val was observed at an allele frequency of 0.03% (18/66,664) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. APC Ile2573Val occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in the EB1 binding domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Ile2573Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000163980 SCV000821826 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000122803 SCV000166060 uncertain significance Familial adenomatous polyposis 1 2018-06-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 2573 of the APC protein (p.Ile2573Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs145444830, ExAC 0.03%). This variant has been reported in individuals affected with multiple colorectal polyps (PMID: 18199528). It has also been observed in an individual affected with numerous adenomatous polyps (Invitae) who also had a pathogenic variant in APC, which suggests that this c.7717A>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 41536). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000236063 SCV000538305 uncertain significance not specified 2017-01-24 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 2 individuals with colorectal adenomas and 1 individual with no cancer. The variant has a Max MAF of 0.03% in ExAC (18 alleles) and 0.02% in gnomAD (21 alleles). Frequency too high for disease? It is classified with 2 stars in ClinVar as VUS by Invitae, Ambry, GeneDx, CSER_CC_NCGL, and Biesecker lab. 10 non-mammals have a Val at this position.
PreventionGenetics RCV000034421 SCV000805470 uncertain significance not provided 2018-01-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236063 SCV000600159 uncertain significance not specified 2017-03-03 criteria provided, single submitter clinical testing

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