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 2018-11-14 criteria provided, single submitter clinical testing Other data supporting benign classification;Subpopulation frequency in support of 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 likely benign Familial adenomatous polyposis 1 2020-12-06 criteria provided, single submitter clinical testing
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 Health, Inc RCV000131588 SCV000681816 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-04 criteria provided, single submitter clinical testing This missense variant replaces glycine with cysteine at codon 2227 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant not been reported in individuals affected with suspected Lynch syndrome, ovarian cancer, and ductal carcinoma in situ (PMID: 24448499, 25980754, 26845104) This variant has been identified in 19/281490 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 RCV000211929 SCV000694100 likely benign not specified 2020-12-25 criteria provided, single submitter clinical testing Variant summary: APC c.6679G>T (p.Gly2227Cys) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251206 control chromosomes, predominantly at a frequency of 0.00011 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 1.5 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.6679G>T has been reported in the literature in various settings of individuals undergoing multigene cancer testing (example, He_2016, Puri_2014, Shirts_2015, Yurgelun_2015, Tung_2015, Gordon_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2, VUS, n=7). Based on the absence of any evidence supporting an actionable outcome spanning 5 years of review as outlined above, the variant was re-classified as likely 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 mad.broadinstitute.org; 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.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761050 SCV000890965 uncertain significance Myeloid Leukemia Associated with Down Syndrome 2016-04-27 criteria provided, single submitter clinical testing

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