ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.53C>T (p.Pro18Leu) (rs79777494)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129344 SCV000184108 benign Hereditary cancer-predisposing syndrome 2017-04-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign) ,General population or sub-population frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Biesecker Lab/Human Development 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.
Color RCV000129344 SCV000910561 benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000121605 SCV000592673 uncertain significance not specified 2014-04-16 criteria provided, single submitter clinical testing
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.
ITMI RCV000121605 SCV000085802 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000123151 SCV000166455 benign MYH-associated polyposis 2018-01-09 criteria provided, single submitter clinical testing
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
PreventionGenetics RCV000121605 SCV000806362 benign not specified 2017-08-02 criteria provided, single submitter clinical testing
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000123151 SCV000267406 uncertain significance MYH-associated polyposis 2016-03-18 criteria provided, single submitter reference population

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