ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4395T>A (p.Ser1465Arg) (rs779898882)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198718 SCV000254015 likely benign Familial adenomatous polyposis 1 2020-11-23 criteria provided, single submitter clinical testing
GeneDx RCV000766728 SCV000293401 uncertain significance not provided 2018-05-23 criteria provided, single submitter clinical testing This variant is denoted APC c.4395T>A at the cDNA level, p.Ser1465Arg (S1465R) at the protein level, and results in the change of a Serine to an Arginine (AGT>AGA). This variant has been identified in a cohort of affected individuals undergoing multi-gene cancer panel testing (Wong 2015). APC Ser1465Arg was not observed at a significant frequency in large population cohorts (Lek 2016). Since Serine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Ser1465Arg is located in the 20 amino acid repeat beta-catenin down-regulating 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 Ser1465Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000446409 SCV000537583 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-27 criteria provided, single submitter clinical testing This missense variant replaces serine with arginine at codon 1465 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with an unspecified cancer (PMID: 25742471). This variant has been identified in 4/251176 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.
Ambry Genetics RCV000446409 SCV000579788 likely benign Hereditary cancer-predisposing syndrome 2020-09-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236990 SCV000600100 uncertain significance not specified 2017-05-08 criteria provided, single submitter clinical testing
Counsyl RCV000198718 SCV000784952 uncertain significance Familial adenomatous polyposis 1 2017-02-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000236990 SCV001478762 uncertain significance not specified 2021-01-30 criteria provided, single submitter clinical testing Variant summary: APC c.4395T>A (p.Ser1465Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251176 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4395T>A has been reported in the literature in individuals affected with breast cancer but not in the setting of familial adenomatous polyposis (example, Gurda_2017, Bonache_2018). 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. Six 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=4), some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.

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