ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3161A>C (p.His1054Pro) (rs777538550)

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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 RCV000217896 SCV000276699 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000232950 SCV000282731 uncertain significance Familial adenomatous polyposis 1 2018-09-18 criteria provided, single submitter clinical testing This sequence change replaces histidine with proline at codon 1054 of the APC protein (p.His1054Pro). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and proline. This variant is present in population databases (rs777538550, ExAC 0.02%). This variant has been reported in an individual who underwent genetic testing for Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 232540). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000657005 SCV000292787 uncertain significance not provided 2019-01-15 criteria provided, single submitter clinical testing This variant is denoted APC c.3161A>C at the cDNA level, p.His1054Pro (H1054P) at the protein level, and results in the change of a Histidine to a Proline (CAC>CCC). This variant was observed in an individual undergoing multigene panel testing for a history of Lynch syndrome associated cancer and/or polyps (Yurgelun 2015). APC His1054Pro was observed at an allele frequency of 0.01% (5/30774) in individuals of South Asian ancestry in large population cohorts (Lek 2016). Since Histidine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC His1054Pro is located in the 15-amino acid repeat beta-catenin binding domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC His1054Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000232950 SCV000489062 uncertain significance Familial adenomatous polyposis 1 2016-08-22 criteria provided, single submitter clinical testing
Color RCV000217896 SCV000681581 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000236039 SCV000731392 uncertain significance not specified 2017-02-21 criteria provided, single submitter clinical testing The p.His1054Pro variant in APC has been reported in one individual with a histo ry of Lynch syndrome-associated cancer and/or polyps who underwent genetic testi ng for Lynch syndrome (Yurgelun 2015) and has also been reported in ClinVar (Va riation ID 232540). In addition, this variant has also been identified in 3/164 56 of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://; dbSNP rs777538550). Computational prediction tools and conservation analysis suggest that the p.His1054Pro variant may impact the prote in, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.His1054Pro variant is uncertain.

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