ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.1640del (p.Ala547fs) (rs587780086)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115764 SCV000149673 uncertain significance not provided 2014-02-21 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1640delC at the cDNA level and p.Ala547GlufsX24 (A547EfsX24) at the protein level. The normal sequence, with the base that is deleted in brackets, is AGTG[C]AGCC. The deletion causes a frameshift in codon 547, which changes an Alanine to a Glutamic Acid, resulting in in the loss of a native stop codon, replacing the last 3 amino acids and likely causing the protein to be extended by 20 more amino acids on the new reading frame. MUTYH Ala547GlufsX24 has not, to our knowledge, been published in the literature as pathogenic or benign. This variant has not been observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Despite the frameshift nature of this variant, its location at the end of the protein might not cause a deleterious effect on protein structure or function. Therefore, with the data currently available, we consider MUTYH Ala547GlufsX24 to be a variant of uncertain significance.
Invitae RCV000200142 SCV000253864 uncertain significance MYH-associated polyposis 2020-09-11 criteria provided, single submitter clinical testing This sequence change results in a frameshift in the MUTYH gene (p.Ala547Glufs*24). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3 amino acids of the MUTYH protein and extend the protein by an additional 20 amino acids. This variant is present in population databases (rs587780086, ExAC 0.001%). This variant has not been reported in the literature in individuals with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 127843). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. 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.
Counsyl RCV000200142 SCV000487313 uncertain significance MYH-associated polyposis 2015-11-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000572345 SCV000676155 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-30 criteria provided, single submitter clinical testing The c.1640delC variant, located in coding exon 16 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 1640, causing a translational frameshift with a predicted alternate stop codon (p.A547Efs*24). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of MUTYH, is not expected to trigger nonsense-mediated mRNA decay, and results in the elongation of the protein by 20 amino acids. This variant has been detected in a patient diagnosed with 1-10 adenomas before age 61y (Baert-Desurmont S et al. Eur J Hum Genet. 2018 Nov;26(11):1597-1602). This alteration has also been detected in a biallelic state in multiple patients with polyposis (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV000572345 SCV000905847 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-27 criteria provided, single submitter clinical testing

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