Submissions for variant NM_001048174.2(MUTYH):c.1079T>C (p.Leu360Pro)

dbSNP: rs1060501335

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465018	SCV000545761	pathogenic	Familial adenomatous polyposis 2	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 388 of the MUTYH protein (p.Leu388Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adenomatous polyposis (PMID: 16134147, 16941501, 17949294). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1121 T>C, p.Leu374Pro, and p.L360P. ClinVar contains an entry for this variant (Variation ID: 406845). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MUTYH function (PMID: 20848659, 23322991, 25820570). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000465018	SCV000697667	likely pathogenic	Familial adenomatous polyposis 2	2021-07-26	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1163T>C (p.Leu388Pro) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250094 control chromosomes (gnomAD and publications). c.1163T>C has been reported in the literature in compound heterozygous individuals affected with MUTYH-Associated Polyposis (e.g. Aceto_2005, Lejeune_2006). These data indicate that the variant is likely to be associated with disease. Experimental evidence demonstrated the variant severely impacts protein activity (e.g. Goto_2010, Shinmura_2012, Komine_2015). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000771347	SCV000903631	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-03-27	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 388 of the MUTYH protein. This variant is also known as p.Leu360Pro and p.Leu374Pro based on alternate transcripts. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant impairs DNA glycosylase activity (PMID: 20848659) and ability to suppress spontaneous mutation (PMID: 23322991, 25820570). This variant has been reported in compound heterozygosity with known pathogenic mutations in multiple individuals affected with adenomatous polyposis (PMID: 16134147, 16941501, 26511139). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics	RCV000771347	SCV001170213	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	The p.L388P pathogenic mutation (also known as c.1163T>C), located in coding exon 12 of the MUTYH gene, results from a T to C substitution at nucleotide position 1163. The leucine at codon 388 is replaced by proline, an amino acid with similar properties. This alteration has been identified in one individual with approximately 40 colorectal adenomas in conjunction with a pathogenic founder mutation in MUTYH; the authors report this patient had no detectable APC mutation and that family studies confirmed these MUTYH alterations to be in trans, but did not provide further details (Aceto G et al. Hum. Mutat. 2005 Oct; 26(4):394). This alteration has been identified in several other individuals with multiple polyps; however, phase was not determined and specific clinical information including polyp count was not provided (Lejeune S et al. Hum. Mutat. 2006 Oct; 27(10):1064; Olschwang S et al. Genet. Test. 2007; 11(3):315-20). This alteration has also been detected in conjunction with another pathogenic mutation in MUTYH by our laboratory, but phase is unknown (Ambry internal data). Various functional assays designed to measure base excision repair function have found this alteration to result in a severely deficient protein (Goto M et al. Hum. Mutat. 2010 Nov; 31(11):E1861-74; Shinmura K et al. World J. Gastroenterol. 2012 Dec; 18(47):6935-42; Komine K et al. Hum. Mutat. 2015 Jul; 36(7):704-11). Of note, this alteration is also designated as p.L360P and p.L374P in published literature. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Sema4, Sema4	RCV000771347	SCV002532206	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-14	criteria provided, single submitter	curation
Baylor Genetics	RCV000465018	SCV005056066	pathogenic	Familial adenomatous polyposis 2	2024-01-17	criteria provided, single submitter	clinical testing
GeneDx	RCV004701495	SCV005202009	pathogenic	not provided	2023-07-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: severely impaired glycosylase activity, base excision repair activity, and suppression of oxidative mutagenesis (Goto et al., 2010; Shinmura et al., 2012; Komine et al., 2015); Co-observed, phase unspecified, with a MUTYH nonsense variant in an individual with multiple colon polyps (Lejeune et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also reported as c.1121T>C p.Leu374Pro using nomenclature from the alternate transcript NM_001048171; This variant is associated with the following publications: (PMID: 23108399, 26511139, 25820570, 23605219, 21777424, 23507534, 25124163, 23322991, 20848659, 19725997, 17949294, 16134147, 16941501)