ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.1588G>T (p.Asp530Tyr) (rs147923905)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586335 SCV000211394 uncertain significance not provided 2018-09-06 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1588G>T at the cDNA level, p.Asp530Tyr (D530Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAT>TAT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MUTYH Asp530Tyr was observed at an allele frequency of 0.01% (8/66738) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the PCNA binding domain (Parker 2001, Ruggieri 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MUTYH Asp530Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.?
Invitae RCV000205460 SCV000260471 uncertain significance MYH-associated polyposis 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 530 of the MUTYH protein (p.Asp530Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs147923905, ExAC 0.01%). This variant has not been reported in the literature in individuals with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 182685). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000219550 SCV000274212 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-16 criteria provided, single submitter clinical testing The p.D530Y variant (also known as c.1588G>T), located in coding exon 16 of the MUTYH gene, results from a G to T substitution at nucleotide position 1588. The aspartic acid at codon 530 is replaced by tyrosine, an amino acid with highly dissimilar properties. In one study, this variant was not detected in 165 colorectal cancer and/or polyposis patients and was identified in 2/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum. Genet., 2018 Oct;137:795-806). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000219550 SCV000685599 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-10 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with tyrosine at codon 530 of the MUTYH protein. This variant is also known as c.1546G>T (p.Asp516Tyr) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 19/282892 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586335 SCV000697687 uncertain significance not provided 2016-01-25 criteria provided, single submitter clinical testing Variant summary: The c.1588G>T variant affects a conserved nucleotide, resulting in amino acid change from Asp to Tyr. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant is found in 9/121408 control chromosomes at a frequency of 0.0000741, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0055902). One clinical laboratory classified this variant as VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
PreventionGenetics,PreventionGenetics RCV000586335 SCV000806350 uncertain significance not provided 2017-01-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586335 SCV001134472 uncertain significance not provided 2019-03-22 criteria provided, single submitter clinical testing

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