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 2020-10-19 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 C1). 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. 5
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 2020-03-12 criteria provided, single submitter clinical testing The p.D2821G variant (also known as c.8462A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 8462. The aspartic acid at codon 2821 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer diagnosed over age 50 who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 Health, Inc RCV000567493 SCV000903243 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-08 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with glycine at codon 2821 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 been reported in an individual affected with breast cancer (PMID: 26976419) and in an individual affected with acute lymphoblastic leukemia (PMID: 26580448). This variant has been identified in 10/271548 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779724 SCV000916485 likely benign not specified 2021-01-11 criteria provided, single submitter clinical testing Variant summary: APC c.8462A>G (p.Asp2821Gly) results in a non-conservative amino acid change located in the EB-1 binding domain (IPR009232) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 240150 control chromosomes, predominantly at a frequency of 0.00044 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8462A>G has been reported in the literature in an individual affected with breast cancer (Tung_2016) and as a likely benign variant in an individual with BCR-ABL rearrangement positive ALL (Zhang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. At-least two co-occurrences with other pathogenic variant(s) have been observed at our laboratory (PALB2 c.172_175delTTGT, p.Gln60fsX7 and MLH1 c.199G>A , p.Gly67Arg), providing additional supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was re-classified as likely benign.

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