ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7468G>A (p.Asp2490Asn) (rs538230198)

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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 RCV000128974 SCV000172860 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000409539 SCV000488075 uncertain significance Familial adenomatous polyposis 1 2015-12-22 criteria provided, single submitter clinical testing
Invitae RCV000409539 SCV000552737 uncertain significance Familial adenomatous polyposis 1 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 2490 of the APC protein (p.Asp2490Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs538230198, ExAC 0.007%). This variant has been reported in the literature in individuals undergoing Lynch syndrome testing (PMID: 25980754) and an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 140800). 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.
GeneDx RCV000656750 SCV000564583 uncertain significance not provided 2017-09-08 criteria provided, single submitter clinical testing This variant is denoted APC c.7468G>A at the cDNA level, p.Asp2490Asn (D2490N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). This variant has been identified in at least one individual with a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). APC Asp2490Asn was observed at an allele frequency of 0.008% (5/66,714) in individuals of European (Non-Finnish) ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Asp2490Asn occurs at a position that is conserved through mammals and is not located in a known functional domain. 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 Asp2490Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000481415 SCV000591208 uncertain significance not specified 2016-07-06 criteria provided, single submitter clinical testing
Color RCV000128974 SCV000681867 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656750 SCV001133367 uncertain significance not provided 2019-07-24 criteria provided, single submitter clinical testing

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