Submissions for variant NM_001048174.2(MUTYH):c.479_492+1del

dbSNP: rs766553845

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000640379	SCV000761970	uncertain significance	Familial adenomatous polyposis 2	2023-04-28	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 533312). This variant is also known as c.563_576+1del. This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is present in population databases (rs766553845, gnomAD 0.0009%). This variant, c.562_576del, results in the deletion of 5 amino acid(s) of the MUTYH protein (p.Glu188_Lys192del), but otherwise preserves the integrity of the reading frame.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780504	SCV000917810	uncertain significance	not specified	2018-08-01	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.563_576+1del involves the deletion of 15 nucleotides from exon 7 and intron 7, leading to an in-frame deletion of 5 amino acids (p.Glu188_Lys192del). 5/5 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 4.1e-06 in 246264 control chromosomes (gnomAD). 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.563_576+1del in individuals affected with MUTYH-associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV001024342	SCV001186341	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-16	criteria provided, single submitter	clinical testing	The c.563_576+1del15 intronic variant, located between coding exon 7 and intron 7 of the MUTYH gene, results from a deletion of the last 14 nucleotides of coding exon 7 and the first nucleotide within intron 7 of the MUTYH gene. This alteration has been detected in conjunction with the MUTYH p.G369D mutation in a patient with early-onset colorectal cancer and polyposis (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, the impacted region is critical for protein function (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000640379	SCV004848013	pathogenic	Familial adenomatous polyposis 2	2016-10-20	criteria provided, single submitter	clinical testing	The c.563_576+1del variant in MUTYH has not been previously reported in individuals with adenomatous polyposis, but has been identified in 1/66736 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs766553845). However, this frequency is low enough to be consistent with the frequency of MUTYH-related attenuated familial adenomatous polyposis (FAP) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 188 and leads to a premature termination codon 60 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Homozygous loss of function of the MUTYH gene is an established disease mechanism in individuals with MUTYH-related attenuated FAP. In summary, this variant meets criteria to be classified as pathogenic for MUTYH-related attenuated FAP in an autosomal recessive manner.