Submissions for variant NM_001048174.2(MUTYH):c.1017dup (p.Arg340fs)

dbSNP: rs768130289

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165254	SCV000215970	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-03	criteria provided, single submitter	clinical testing	The c.1101dupC pathogenic mutation, located in coding exon 12 of the MUTYH gene, results from a duplication of C at nucleotide position 1101, causing a translational frameshift with a predicted alternate stop codon (p.R368Qfs*164). This alteration has been detected in conjunction with another MUTYH mutation in patients diagnosed with colorectal cancer and/or polyps (Lejeune S. et al. Hum Mutat. 2006 Oct;27(10):1064; Castillejo A et al. Eur J Cancer. 2014 Sep;50(13):2241-50). This alteration as also been detected as monoallelic in patients diagnosed with breast or ovarian cancer (Bonache S et al. J Cancer Res Clin Oncol. 2018 Oct 10). This variant is designated as 1059dupC in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000485059	SCV000568580	likely pathogenic	not provided	2017-01-04	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in MUTYH is denoted c.1101dupC at the cDNA level and p.Arg368GlnfsX164 (R368QfsX164) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GCCCCC[dupC]AGGG. The duplication causes a frameshift which changes an Arginine to a Glutamine at codon 368, and creates a premature stop codon at position 164 of the new reading frame. Even though nonsense-mediated decay is not expected to occur due to the position of the variant, it is significant since the last 182 amino acids are no longer translated correctly and are replaced by 163 incorrect ones. This variant is predicted to cause loss of normal protein function through protein truncation. MUTYH Arg368GlnfsX164 has been reported in the compound heterozygous state with a pathogenic MUTYH variant in an individual with colorectal and breast cancer (Castillejo 2014). Based on the currently available information, we consider this duplication to be a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688652	SCV000816274	pathogenic	Familial adenomatous polyposis 2	2023-09-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg368Glnfs*164) in the MUTYH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 182 amino acid(s) of the MUTYH protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with attenuated familial adenomatous polyposis and colon and breast cancer (PMID: 16941501, 24953332). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1059dupC (Arg354Glnfs*164). ClinVar contains an entry for this variant (Variation ID: 185770). This variant disrupts the conserved PCNA binding motif of the MUTYH protein, which has been shown to be critical for MUTYH-PCNA binding and repair efficiency (PMID: 11092888, 26377631, 11433026, 11864576). While functional studies have not been performed to directly test the effect of this variant on MUTYH protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000165254	SCV000905857	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-26	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 12 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as c.1059dupC (Arg354Glnfs*164). This variant has been observed in biallelic individuals affected with colorectal cancer and/or polyposis (PMID: 16941501, 24953332, 33130102). This variant has been identified in 1/250124 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000688652	SCV002014923	pathogenic	Familial adenomatous polyposis 2	2021-10-15	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1101dupC (p.Arg368GlnfsX164) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 250124 control chromosomes (gnomAD). c.1101dupC has been reported in the literature in compound heterozygous individuals affected with MUTYH-Associated Polyposis or colorectal cancer (e.g. Lejeune_2006, Castillejo_2014, Thomas_2021). In addition, the variant has been reported in heterozygous individuals affected with breast and ovarian cancer (e.g. Bonache_2018, Feliubadalo_2019, Ramirez-Calvo_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000688652	SCV004840817	pathogenic	Familial adenomatous polyposis 2	2024-02-05	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 12 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as c.1059dupC (Arg354Glnfs*164). This variant has been observed in biallelic individuals affected with colorectal cancer and/or polyposis (PMID: 16941501, 24953332, 33130102). This variant has been identified in 1/250124 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.