ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.11C>T (p.Pro4Leu) (rs79777494)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123151 SCV000166455 benign MYH-associated polyposis 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129344 SCV000184108 benign Hereditary cancer-predisposing syndrome 2017-04-03 criteria provided, single submitter clinical testing General population or sub-population frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign)
GeneDx RCV000121605 SCV000211395 uncertain significance not specified 2017-09-26 criteria provided, single submitter clinical testing The MUTYH c.53C>T variant was individually examined in a bacterial complementation assay, and was found to result in partially defective base excision repair activity (Komine 2015). MUTYH Pro18Leu was observed with an allele frequency of 1.3% (114/8654 alleles) in individuals of East Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. MUTYH Pro18Leu occurs at a position that is not conserved and is located in the RPA binding domain (Ruggieri 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MUTYH Pro18Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000123151 SCV000267406 uncertain significance MYH-associated polyposis 2016-03-18 criteria provided, single submitter reference population
Laboratory for Molecular Medicine,Partners HealthCare 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,PreventionGenetics RCV000121605 SCV000806362 benign not specified 2017-08-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129344 SCV000910561 benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Mendelics RCV000123151 SCV001135269 benign MYH-associated polyposis 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034676 SCV001147276 likely benign not provided 2021-01-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282496 SCV001159516 benign none provided 2019-09-29 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000123151 SCV001257716 uncertain significance MYH-associated polyposis 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 uncertain significance not provided 2020-08-09 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.

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