ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.722G>A (p.Arg241Gln) (rs1060501346)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000584291 SCV000690604 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-07 criteria provided, single submitter clinical testing
Invitae RCV000459400 SCV000545803 likely pathogenic MYH-associated polyposis 2018-05-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 241 of the MUTYH protein (p.Arg241Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported with a second pathogenic MUTYH variant (p.Gly396Asp) in an individual with polyposis (100-500 polyps) and colorectal cancer (PMID: 19732775). In addition, this variant has been observed as homozygous in individuals with polyposis or colon cancer (PMID: 21520333, Invitae). ClinVar contains an entry for this variant (Variation ID: 406867). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Arg241Trp, also known as p.Arg227Trp in the literature) has been determined to be pathogenic (PMID: 15673720, 25820570, 24470512, 14991577, 27194394, Invitae). This suggests that the arginine residue is critical for MUTYH protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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