Submissions for variant NM_001048174.2(MUTYH):c.1556del (p.Ala519fs)

gnomAD frequency: 0.00001  dbSNP: rs587780086

Total submissions: 7

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200142	SCV000253864	likely pathogenic	Familial adenomatous polyposis 2	2023-10-15	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 acid(s) of the MUTYH protein and extend the protein by 20 additional amino acid residues. This variant is present in population databases (rs587780086, gnomAD 0.004%). This frameshift has been observed in individual(s) with MUTYH-associated polyposis (PMID: 34704405; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 127843). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl	RCV000200142	SCV000487313	uncertain significance	Familial adenomatous polyposis 2	2015-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000572345	SCV000676155	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-09-26	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 61 (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 Diagnostics, LLC DBA Color Health	RCV000572345	SCV000905847	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000200142	SCV004198919	uncertain significance	Familial adenomatous polyposis 2	2023-07-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000200142	SCV004827713	uncertain significance	Familial adenomatous polyposis 2	2023-08-15	criteria provided, single submitter	clinical testing