ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5690A>C (p.His1897Pro) (rs112610898)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130647 SCV000185526 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-30 criteria provided, single submitter clinical testing The p.H1897P variant (also known as c.5690A>C), located in coding exon 15 of the APC gene, results from an A to C substitution at nucleotide position 5690. The histidine at codon 1897 is replaced by proline, an amino acid with similar properties. This alteration has been reported in the literature as a variant of uncertain significance in an individual who had a co-occurring pathogenic Lynch Syndrome mutation: MSH2 c.1511-1G>A (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-613.e20). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000198116 SCV000254026 benign Familial adenomatous polyposis 1 2020-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000586043 SCV000292461 uncertain significance not provided 2018-02-09 criteria provided, single submitter clinical testing This variant is denoted APC c.5690A>C at the cDNA level, p.His1897Pro (H1897P) at the protein level, and results in the change of a Histidine to a Proline (CAC>CCC). This variant has been observed in an individual undergoing multigene cancer panel testing due to a personal history of a Lynch syndrome-associated cancer and/or polyps who was also found to harbor a pathogenic MSH2 variant (Yurgelun 2015). APC His1897Pro was observed at an allele frequency of 0.1% (24/24,010) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the 20-aa repeat B-catenin down-regulating domain and the SAMP repeats/axin 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 His1897Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000130647 SCV000681756 likely benign Hereditary cancer-predisposing syndrome 2020-01-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586043 SCV000694083 likely benign not provided 2016-07-25 criteria provided, single submitter clinical testing Variant summary: The APC c.5690A>C (p.His1897Pro) variant involves the alteration of a conserved nucleotide. It is not present in a known domain till date. 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant was found in 10/120962 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0008699 (9/10346). This frequency is about 12 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Multiple clinical diagnostic laboratories have classified this variant as uncertain significance without evidence to independently evaluate. The variant of interest has been reported in one subject with suspected Lynch syndrome who also carried MSH2 c.1511-1G>A and BRIP1 p.His478Arg, supporting for the benign outcome (Yurgelun_2015). Taken together, this variant is currently classified as Likely Benign.
Counsyl RCV000198116 SCV000785298 uncertain significance Familial adenomatous polyposis 1 2017-06-30 criteria provided, single submitter clinical testing
Mendelics RCV000198116 SCV000838135 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing

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