ClinVar Genomic variation as it relates to human health

This variant is associated with the following publications: (PMID: 24728327, 21167187, 25820570, 22703879, 21153778, 28944238)

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Converted during submission to Benign.

The MUTYH p.Leu529Met variant was identified in the literature, although the frequency of this variant in an affected population was not provided. The variant was identified in dbSNP (rs3219496) as “with other allele”, ClinVar (classified as likely benign by Ambry Genetics, GeneDx, Pathway Genomics and 3 other submitters; and as benign by Invitae, Color, PreventionGenetics and 2 other submitters). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 893 of 282,882 chromosomes (16 homozygous) at a frequency of 0.003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 852 of 35,440 chromosomes (freq: 0.02), Other in 16 of 7226 chromosomes (freq: 0.002), African in 15 of 24,966 chromosomes (freq: 0.0006), East Asian in 3 of 19,954 chromosomes (freq: 0.0002), European in 6 of 129,186 chromosomes (freq: 0.00005), and South Asian in 1 of 30,616 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish or Finnish populations. Site-directed mutagenesis experiments demonstrated that the variant did not alter the functional activity of MUTYH in E. coli cells (Komine 2015). The p.Leu529 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.