ClinVar Miner

Submissions for variant NM_000038.6(APC):c.220G>T (p.Glu74Ter) (rs876658941)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215333 SCV000274815 pathogenic Hereditary cancer-predisposing syndrome 2016-08-18 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000254875 SCV000322197 likely pathogenic not provided 2016-11-08 criteria provided, single submitter clinical testing This variant is denoted APC c.220G>T at the cDNA level. Located in the last nucleotide of exon 3, it destroys a natural splice donor site and causes abnormal splicing. RNA analyses by Schwarzova et al. (2013) demonstrated that this variant results in skipping of exon 3, referred to as exon 2 using alternate nomenclature, as well as a second alternate transcript with skipping of exons 3 and 4 (also known as exons 2 and 3). These alternate transcripts may result in the production of some functional protein by using an alternate downstream AUG start codon at position 184. APC proteins produced from this alternate start codon have been shown to have normal cellular localization and ability to regulate B-catenin levels, which may explain the attenuated phenotype seen in some patients with 5' truncating APC variants (Heppner Goss 2002). APC c.220G>T has been seen in at least one individual with colorectal cancer who was reported to have attenuated familial adenomatous polyposis (AFAP), though the number of polyps was not described (Stekrova 2007). Although the nucleotide substitution is predicted to result in the change of a Glutamic Acid to a premature stop codon, and is called Glu74Ter in the literature, we are only using the nucleotide nomenclature to refer to the variant since it is not clear if any truncated protein from the premature stop codon is translated or if the observed abnormal splicing mitigates the effect of the premature stop codon. APC c.220G>T was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Based on currently available evidence, we consider APC c.220G>T to be a likely pathogenic variant.
Invitae RCV000459175 SCV000552521 likely pathogenic Familial adenomatous polyposis 1 2019-09-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 74 (p.Glu74*) of the APC gene. It also falls at the last nucleotide of exon 3 of the APC coding sequence. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APC are known to be pathogenic. This particular variant has been reported in the literature in an individual with attenuated adenomatous polyposis (AFAP) (PMID: 17411426). ClinVar contains an entry for this variant (Variation ID: 231074). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). This variant has been shown to result in skipping of exon 2 in patient cells, however the level of alternatively spliced mRNA versus truncated product consisting only of exons 1-3 was not quantified, and the effect of exon 2 skipping on APC protein expression and function is unknown. The level of expression of all alternative mRNA products was reduced compared to healthy control individuals (PMID: 22987206.) In summary, this variant leads to absence or disruption of functional APC protein. However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000501460 SCV000591020 pathogenic Familial adenomatous polyposis 2016-11-23 criteria provided, single submitter clinical testing

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