ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4732T>G (p.Cys1578Gly) (rs138367627)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129037 SCV000172947 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-30 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Structural Evidence
Invitae RCV000206222 SCV000260260 likely pathogenic Familial adenomatous polyposis 1 2019-12-06 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 1578 of the APC protein (p.Cys1578Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of familial adenomatous polyposis (PMID: 18199528, Invitae). ClinVar contains an entry for this variant (Variation ID: 140839). This variant has been reported to have conflicting or insufficient data to determine the effect on APC protein (PMID: 18199528). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV000236515 SCV000293423 likely pathogenic not provided 2018-09-25 criteria provided, single submitter clinical testing This variant is denoted APC c.4732T>G at the cDNA level, p.Cys1578Gly (C1578G) at the protein level, and results in the change of a Cysteine to a Glycine (TGT>GGT). This variant has been identified in at least one individual with multiple colorectal adenomas (Azzopardi 2008). APC Cys1578Gly was not observed in large population cohorts (Lek 2016). This variant is located in 20-aa repeat Beta-catenin down-regulating domain and the SAMP repeats/axin binding domain (Azzopardi 2008). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider APC Cys1578Gly to be a likely pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507260 SCV000602503 uncertain significance not specified 2019-05-18 criteria provided, single submitter clinical testing The APC c.4732T>G; p.Cys1578Gly variant (rs138367627) is reported in the literature in an individual affected with multiple colorectal adenomas (Azzopardi 2008). This variant is found on a single chromosome (1/250924 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The cysteine at codon 1578 is highly conserved across species, located in the SAMP repeats/axin binding domain (Azzopardi 2008), and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, in functional assays, the p.Cys1578Gly variant suppressed beta-catenin-regulated transcription to the same extent as wildtype protein (Azzopardi 2008). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Azzopardi D et al. Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas. Cancer Res. 2008 Jan 15;68(2):358-63.
Integrated Genetics/Laboratory Corporation of America RCV000507260 SCV000918486 uncertain significance not specified 2019-10-21 criteria provided, single submitter clinical testing Variant summary: APC c.4732T>G (p.Cys1578Gly) results in a non-conservative amino acid change located in the SAMP repeats/axin binding domain (Azzopardi 2008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Five predict the variant creates a cryptic 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250924 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4732T>G has been reported in the literature in one individual affected with colorectal adenomas (Azzopard_2008). The report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Azzopard_2008). Four ClinVar submitter (evaluation after 2014) cite the variant as likely pathogenic (2x) and uncertain significance (2x). Based on the evidence outlined above, the variant was classified as uncertain significance.
CSER _CC_NCGL, University of Washington RCV000148367 SCV000190059 uncertain significance Colorectal adenoma 2014-06-01 no assertion criteria provided research

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