ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7088A>G (p.Lys2363Arg)

gnomAD frequency: 0.00002  dbSNP: rs587779806
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115119 SCV000149028 uncertain significance not provided 2015-06-23 criteria provided, single submitter clinical testing This variant is denoted APC c.7088A>G at the cDNA level, p.Lys2363Arg (K2363R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Lys2363Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. APC Lys2363Arg occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located in the basic domain and the Ser-rich region (Azzopardi 2008, UniProt) In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC Lys2363Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV004562266 SCV000282811 uncertain significance Familial adenomatous polyposis 1 2024-08-06 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 2363 of the APC protein (p.Lys2363Arg). This variant is present in population databases (rs587779806, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 127317). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. 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 RCV001026018 SCV001188318 likely benign Hereditary cancer-predisposing syndrome 2022-09-22 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health RCV003997229 SCV004837594 uncertain significance Classic or attenuated familial adenomatous polyposis 2024-07-20 criteria provided, single submitter clinical testing This missense variant replaces lysine with arginine at codon 2363 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 4/249580 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics RCV004562266 SCV005055187 uncertain significance Familial adenomatous polyposis 1 2024-01-24 criteria provided, single submitter clinical testing

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