Description
Variant summary: MUTYH c.1276C>T (p.Arg426Cys) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00081 in 252980 control chromosomes, predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.00081 vs 0.0046), allowing no conclusion about variant significance. c.1276C>T has been reported in multiple FAP or attenuated FAP patients in monoallelic state (e.g. Aceto_2005, Aretz_2006, de Lyon_2013, Ricci_2017, Sulova_2009). Furthermore, it has been reported with other pathogenic MUTYH variants in biallelic patients affected with synchronous/metachronous polyps (Lopez-Villar_2010) and colorectal cancer (e.g. De Rycke 2017, Yurgelun 2017). In some of these reports, it was classified as a VUS in settings of multigene cancer panel testing. Additional reports of the variant in individuals with a personal and/or family history of colorectal cancer, HBOC, lung and endometrial cancer have also been published (e.g. Fleischmann_2004, Ricci_2016, Ring_2016, Tung_2016, Martin-Morales_2018, Rizzolo_2018, Oliver_2019, Lin_2019, Tsaousis_2019, Grasel_2020, Pope_2021, Sahin_2022). These data do not allow any conclusion about variant significance. Multiple co-occurrences with other pathogenic variant(s) have been observed at our laboratory (BRCA2 c.4647_4650delAGAG , p.Lys1549fsX18 ; APC c.2161_2170delGGAAGTGCTG, p.Gly721fsX3; MSH6 c.3013C>T, p.Arg1005X; PALB2 c.2386G>T, p.Gly796X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant as evidenced by comparable function to wild-type in terms of suppression of spontaneous mutations (Komine_2015). The following publications have been ascertained in the context of this evaluation (PMID: 22703879, 25820570, 16134147, 16557584, 19531215, 24470512, 20687945, 17524638, 14991577, 26976419, 22976915, 27443514, 28135145, 28944238, 30256826, 30151275, 27829682, 30564557, 30850667, 31159747, 31921681, 31422818, 33383211, 33134171, 35089076, 35430768, 35628513). ClinVar contains an entry for this variant (Variation ID: 41753). Based on the evidence outlined above, the variant was classified as likely benign.
# | Sample | Method | Observation |
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Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
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1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |