ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.32G>A (p.Gly11Asp) (rs75321043)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123155 SCV000166459 benign MYH-associated polyposis 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129347 SCV000184111 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 RCV000121606 SCV000211396 uncertain significance not specified 2017-09-26 criteria provided, single submitter clinical testing The MUTYH c.74G>A variant was individually examined in a bacterial complementation assay,and was found to retain base excision repair activity (Komine 2015). MUTYH Gly25Asp was observed with an allelefrequency of 0.8% (8/1008) in the East Asian populations in 1000 Genomes. Since Glycine and Aspartic Acid differ inpolarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MUTYHGly25Asp occurs at a position that is not conserved and is located in the RPA binding domain (Ruggieri 2013). In silicoanalyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence,it is unclear whether MUTYH Gly25Asp is a pathogenic or benign variant. We consider it to be a variant of uncertainsignificance.
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000123155 SCV000267405 uncertain significance MYH-associated polyposis 2016-03-18 criteria provided, single submitter reference population
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000121606 SCV000539815 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; ClinVar: 4 labs classify as VUS
Color Health, Inc RCV000129347 SCV000690606 benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000034680 SCV000697710 benign not provided 2017-08-21 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.74G>A (p.Gly25Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large and broad cohorts of the ExAC project at an allele frequency of 0.001112 (135/121410 chrs tested), predominantly observed in the East Asian subpopulation (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.53C>T (P18L). 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.
Counsyl RCV000123155 SCV000788437 uncertain significance MYH-associated polyposis 2017-11-13 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000121606 SCV000806367 benign not specified 2017-08-02 criteria provided, single submitter clinical testing
Mendelics RCV000123155 SCV001135267 benign MYH-associated polyposis 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034680 SCV001147275 likely benign not provided 2021-01-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282495 SCV001159515 benign none provided 2019-09-29 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000123155 SCV001257715 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 RCV000034680 SCV001469577 uncertain significance not provided 2020-08-09 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034680 SCV000043379 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
ITMI RCV000121606 SCV000085804 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353637 SCV000592675 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The p.Gly25Asp variant was identified in the literature in 18 of 896 proband chromosomes (frequency: 0.020) from Asian individuals (Korean, Chinese, Japanese) with adenomatous polyposis or colorectal cancer, and was present in 6 of 944 control chromosomes (frequency: 0.006) (Chen 2008, Kim 2007, Yanaru-Fujisawa 2008, Zhang 2006). In all these studies, the variant was identified in co-occurrence on the same allele as another MUTYH variant, p.Pro18Leu. 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. The variant was also identified in dbSNP (ID: rs75321043) “With allele of Uncertain significance” with a minor allele frequency of 0.003 (1000 Genomes Project), in HGMD, and in the “InSiGHT Colon Cancer Database”. The p.Gly25 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. Therefore, this variant is classified as a variant of unknown significance (VUS).

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