ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2627G>A (p.Arg876Gln) (rs373428732)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206834 SCV000262249 benign Familial adenomatous polyposis 1 2020-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000236048 SCV000293033 uncertain significance not provided 2018-02-25 criteria provided, single submitter clinical testing This variant is denoted APC c.2627G>A at the cDNA level, p.Arg876Gln (R876Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism. However, this variant has been reported as a somatic variant in colon and myelodysplastic syndrome tumors (Vasovcak 2011, Seshagiri 2012, Luthra 2014). APC Arg876Gln was observed at an allele frequency of 0.01%, (13/126090) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Arg876Gln is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether APC Arg876Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000206834 SCV000489272 uncertain significance Familial adenomatous polyposis 1 2016-09-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV000491164 SCV000579833 likely benign Hereditary cancer-predisposing syndrome 2020-08-03 criteria provided, single submitter clinical testing No disease association in small case-control study;Subpopulation frequency in support of benign classification
Color Health, Inc RCV000491164 SCV000681541 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-16 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 876 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 hereditary cancer in the literature. This variant has been identified in 15/282206 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.
Mendelics RCV000206834 SCV000838093 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000236048 SCV001154458 uncertain significance not provided 2019-06-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193536 SCV001362433 likely benign not specified 2019-01-18 criteria provided, single submitter clinical testing Variant summary: APC c.2627G>A (p.Arg876Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.8e-05 in 276520 control chromosomes, predominantly at a frequency of 0.0001 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2627G>A has been reported in the literature in an individual with no specific phenotype being provided and was classified as likely benign by the authors (He_2016). This report does not provide an unequivocal conclusion about association of the variant with Familial Adenomatous Polyposis. Co-occurrences with other pathogenic variant(s) have been reported (CHEK2 c.1100delC, p.T367fsX15). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant predominantly as uncertain significance (5x) and once as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

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