ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6679G>T (p.Gly2227Cys) (rs367905430)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131588 SCV000186600 likely benign Hereditary cancer-predisposing syndrome 2017-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,Other data supporting benign classification
GeneDx RCV000590651 SCV000209539 uncertain significance not provided 2019-01-08 criteria provided, single submitter clinical testing This variant is denoted APC c.6679G>T at the cDNA level, p.Gly2227Cys (G2227C) at the protein level, and results in the change of a Glycine to a Cysteine (GGC>TGC). This variant has been observed in at least one individual with DCIS and in 2 individuals with a Lynch syndrome associated cancer and/or polyps undergoing genetic testing using a multi-gene panel (Yurgelun 2015, Shirts 2016). APC Gly2227Cys was observed at an allele frequency of 0.01%(13/126294) in individuals of European ancestry in large population cohorts (Lek 2016). Since Glycine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Gly2227Cys is located in the basic domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether APC Gly2227Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
University of Washington Department of Laboratory Medicine,University of Washington RCV000210106 SCV000266144 uncertain significance Colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000234415 SCV000282800 uncertain significance Familial adenomatous polyposis 1 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 2227 of the APC protein (p.Gly2227Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is present in population databases (rs367905430, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with breast cancer, and in an individual with a history of Lynch syndrome–associated cancer and/or colorectal polyps (PMID: 25980754, 26845104). ClinVar contains an entry for this variant (Variation ID: 142457) Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. 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 RCV000234415 SCV000489145 uncertain significance Familial adenomatous polyposis 1 2016-08-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000211929 SCV000600135 uncertain significance not specified 2017-04-07 criteria provided, single submitter clinical testing
Color RCV000131588 SCV000681816 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590651 SCV000694100 uncertain significance not provided 2017-05-22 criteria provided, single submitter clinical testing Variant summary: The APC c.6679G>T (p.Gly2227Cys) variant located in the Adenomatous polyposis coli protein basic domain (via InterPro) involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome for this variant. This variant was found in 14/121580 control chromosomes at a frequency of 0.0001152, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this variant is likely a benign polymorphism. Multiple publications have cited the variant in affected individuals (Breast cancer, Lynch syndrome, Pancreatic cancer), however, limited information is provided for an independent assessment (ie, lack of co-occurrence, cosegregation, and/or phenotypic data). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Therefore, until additional information becomes available, the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Benign."
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211929 SCV000731351 uncertain significance not specified 2016-12-21 criteria provided, single submitter clinical testing The p.Gly2227Cys variant in APC has been reported in 2 individuals who underwent genetic testing for Lynch syndrome (Yurgelun 2015) and has also been reported i n ClinVar (Variation ID 142457). In addition, it has been identified in 13/12629 4 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gno; dbSNP rs367905430). Computational prediction tools and c onservation analysis suggest that the p.Gly2227Cys variant may impact the protei n, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Gly2227Cys variant is uncertain.
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761050 SCV000890965 uncertain significance Myeloid Leukemia Associated with Down Syndrome 2016-04-27 no assertion criteria provided clinical testing

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