ClinVar Miner

Submissions for variant NM_000038.6(APC):c.8462A>G (p.Asp2821Gly) (rs780049836)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000196318 SCV000254051 uncertain significance Familial adenomatous polyposis 1 2018-12-29 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 2821 of the APC protein (p.Asp2821Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs780049836, ExAC 0.02%). This variant has been reported in individuals affected with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 21688). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
Counsyl RCV000196318 SCV000488662 uncertain significance Familial adenomatous polyposis 1 2016-05-20 criteria provided, single submitter clinical testing
GeneDx RCV000478701 SCV000567439 uncertain significance not provided 2018-07-13 criteria provided, single submitter clinical testing This variant is denoted APC c.8462A>G at the cDNA level, p.Asp2821Gly (D2821G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAC>GGC). This variant has been observed in at least one individual with breast cancer and another with leukemia (Zhang 2015, Tung 2016). APC Asp2821Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the hDLG binding domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Asp2821Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000567493 SCV000667248 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Fulgent Genetics,Fulgent Genetics RCV000765792 SCV000897181 uncertain significance Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000567493 SCV000903243 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779724 SCV000916485 uncertain significance not specified 2017-10-31 criteria provided, single submitter clinical testing Variant summary: The APC c.8462A>G (p.Asp2821Gly) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 10/266080 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.000378 (9/23814). This frequency is about 5 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. This variant has been reported in affected individuals without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS-possibly benign until more evidence becomes available.

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