Submissions for variant NM_001048174.2(MUTYH):c.11C>T (p.Pro4Leu)

gnomAD frequency: 0.00044  dbSNP: rs79777494

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123151	SCV000166455	benign	Familial adenomatous polyposis 2	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129344	SCV000184108	benign	Hereditary cancer-predisposing syndrome	2017-04-03	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000034676	SCV000211395	likely benign	not provided	2021-06-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22703879, 11295288, 22641385, 25980754, 18422726, 18811933, 25525159, 16929514, 25820570, 26684191, 17252231, 27443514, 26332594, 24728327, 17703316, 27600092, 29330641, 29879026, 30333958, 29667044)
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000123151	SCV000267406	uncertain significance	Familial adenomatous polyposis 2	2016-03-18	criteria provided, single submitter	reference population
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121605	SCV000539816	benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 1.3% (114/8654) East Asian chromosomes - common haplotype with Gly25Asp
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034676	SCV000697701	benign	not provided	2017-08-21	criteria provided, single submitter	clinical testing	Variant summary: The MUTYH c.53C>T (p.Pro18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.001112 (135/121410 chrs tested), predominantly in individuals of East Asian descent with a frequency of 0.013 (114/8654 chrs, including 2 homozygotes). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. Most of the published reports indicate that c.74G>A co-occurs in cis with c.74G>A(G25DL). Although c.[53C>T; 74G>A] haplotype has been reported to be enriched in sporadic CRC pts compared to controls (Chen, 2008), in functional studies both the complex allele and its compounds were shown to retain complementation ability and were considered to be functionally neutral. In addition, several reported CRC pts carried known pathogenic variants (APC c.3595_3596delAA (p.Lys1199Glufs), MSH6 c.3724_3726del (p.Arg1242del) , that could have explain CRC phenotype in these families (Taki, 2016, Ring, 2012). Lastly, several reputable databases/diagnostic centers classified the variant of interest as VUS/ Benign. Taking together, by applying ACMG rules, the variant was classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000121605	SCV000806362	benign	not specified	2017-08-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129344	SCV000910561	benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Mendelics	RCV000123151	SCV001135269	benign	Familial adenomatous polyposis 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034676	SCV001147276	benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	MUTYH: BP4, BS1, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034676	SCV001159516	benign	not provided	2023-04-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000123151	SCV001257716	uncertain significance	Familial adenomatous polyposis 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034676	SCV001470575	likely benign	not provided	2023-06-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129344	SCV002532296	benign	Hereditary cancer-predisposing syndrome	2020-08-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121605	SCV002552533	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034676	SCV000043382	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
ITMI	RCV000121605	SCV000085802	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353745	SCV000592673	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MUTYH p.Pro18Leu variant was identified in 20 of 1686 proband chromosomes (frequency: 0.01) from individuals or families from Asian individuals (Korean, Chinese, Japanese) with colorectal, endometrial and adenomatous polyposis cancer (Ring 2016, Taki 2016, Chen 2008, Kim 2007, Yanaru-Fujisawa 2008, Zhang 2006). The variant was also identified in the following databases: dbSNP (ID: rs79777494) as With other allele, ClinVar (classified as benign by Invitae, Ambry Genetics, Integrated Genetics/Laboratory Corporation of America; as uncertain significance by GeneDx, and two clinical laboratories), Clinvitae, COGR, and MutDB. The variant was not identified in Cosmic, or UMD-LSDB databases. The variant was identified in control databases in 288 of 277220 chromosomes (4 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 2 of 6462 chromosomes (freq: 0.0003), European in 4 of 126714 chromosomes (freq: 0.00003), East Asian in 250 of 18870 chromosomes (freq: 0.01), and South Asian in 32 of 30782 chromosomes (freq: 0.001); it was not observed in the African, Latino, Ashkenazi Jewish, or Finnish populations. The p.Pro18 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant was identified in co-occurrence on the same allele as another MUTYH variant, p.Gly25Asp. Two studies suggest that this haplotype variant allele (containing both p.Pro18Leu and p.Gly25Asp variants) increases the risk of gastric cancer, with significantly higher frequencies of the variant haplotype observed in affected cases than in healthy controls (Chen 2008, Zhang 2006). In addition, a functional study by Chen (2008) found that the haplotype variant allele had a partial effect on protein mitochondrial transport as compared to wild type MUTYH protein. This effect, however, was not found when each variant was tested individually, suggesting an additive effect of the combined variants on the mitochondrial targeting sequences domain of the MUTYH protein. In addition, several studies identify the variant co-occurring with known pathogenic variants (APC c.3595_3596delAA (p.Lys1199Glufs), MSH6 c.3724_3726del (p.Arg1242del), increasing the likelihood that the p.Gly25Asp variant does not have clinical significance (Ring 2016, Taki 2016). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.