ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6658A>G (p.Asn2220Asp) (rs374464049)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657112 SCV000293830 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing This variant is denoted APC c.6658A>G at the cDNA level, p.Asn2220Asp (N2220D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAC>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Asn2220Asp was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. APC Asn2220Asp occurs at a position where amino acids with properties similar to Asparagine are tolerated across species and is located in the basic 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 Asn2220Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000564209 SCV000667296 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000236846 SCV000712651 uncertain significance not specified 2016-11-25 criteria provided, single submitter clinical testing The p.Asn2220Asp variant in APC has not been previously reported in individuals with hereditary cancer or in large population studies, but has been identified i n 1/66412 European chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs374464049). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Asn2220Asp variant is uncertain.
Invitae RCV000646323 SCV000768091 uncertain significance Familial adenomatous polyposis 1 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 2220 of the APC protein (p.Asn2220Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs374464049, ExAC 0.002%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 246324). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657112 SCV000887543 uncertain significance not provided 2018-08-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000236846 SCV000916461 uncertain significance not specified 2017-12-04 criteria provided, single submitter clinical testing Variant summary: The APC c.6658A>G (p.Asn2220Asp) variant involves the alteration of a conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant was found in 3/276652 control chromosomes (gnomAD) at a frequency of 0.0000108, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). The variant of interest has not, to our knowledge, been reported in affected individuals via publications. In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.

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