ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1958G>T (p.Arg653Met) (rs1060503318)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000462234 SCV000552633 likely pathogenic Familial adenomatous polyposis 1 2016-10-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with methionine at codon 653 of the APC protein (p.Arg653Met). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and methionine. It also falls at the last nucleotide of exon 15 of the APC coding sequence. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with a diagnosis or clinical suspicion of familial adenomatous polyposis (PMID: 19036155, 25590978, 23159591, 20685668). A different missense substitution at this codon (p.Arg653Lys) has been determined to be pathogenic (PMID: 25590978, 20685668, 24599579). This suggests that the arginine residue is critical for APC protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this missense change induces exon 14 skipping (PMID: 20685668). In summary, this variant is a rare missense change that has been observed in affected individuals and has been shown to affect APC splicing. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000491095 SCV000579887 pathogenic Hereditary cancer-predisposing syndrome 2018-02-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Last nucleotide of exon,Well-characterized mutation at same position,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species

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