ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.38C>T (p.Ala13Val) (rs587780747)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123150 SCV000166453 uncertain significance MYH-associated polyposis 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 13 of the MUTYH protein (p.Ala13Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 135987). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000131635 SCV000186659 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-05 criteria provided, single submitter clinical testing The p.A13V variant (also known as c.38C>T), located in coding exon 2 of the MUTYH gene, results from a C to T substitution at nucleotide position 38. The alanine at codon 13 is replaced by valine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000123150 SCV000487325 uncertain significance MYH-associated polyposis 2015-12-22 criteria provided, single submitter clinical testing
GeneDx RCV000485844 SCV000569382 uncertain significance not provided 2017-01-16 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.38C>T at the cDNA level, p.Ala13Val (A13V) at the protein level, and results in the change of an Alanine to a Valine (GCC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH Ala13Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. MUTYH Ala13Val occurs at a position that is not conserved and is located in the RPA domain (Ruggieri 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available evidence, it is unclear whether MUTYH Ala13Val 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.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000131635 SCV000679734 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131635 SCV000685625 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001260346 SCV001437279 uncertain significance not specified 2020-09-04 criteria provided, single submitter clinical testing Variant summary: MUTYH c.38C>T (p.Ala13Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251466 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.38C>T in individuals affected with MUTYH-Associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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