ClinVar Genomic variation as it relates to human health

Variant summary: The MUTYH c.1449C>T (p.Thr483Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 388/121394 control chromosomes (7 homozygotes), predominantly observed in the South Asian subpopulation at a frequency of 0.0199855 (330/16512). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0055902), suggesting this is a benign polymorphism found primarily in the populations of South Asian origin. For comparison, p.Tyr104Ter is the most common pathogenic South Asian variant and occurs only 14/121398 ExAC chromosomes. The variant was reported in affected individuals in the literature, without any evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

This alteration is classified as likely 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.

The MUTYH p.Thr483= variant was identified in 1 of 162 proband chromosomes (frequency: 0.006) from individuals or families with hereditary non-polyposis colorectal cancer (Morak 2011). The variant was identified dbSNP (rs150269172) as “with other allele” and ClinVar (classified as benign by Invitae, GeneDx, Color and 4 other submitters; and as likely benign by Ambry Genetics, Prevention Genetics and 2 other submitters). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 745 of 277,238 chromosomes (14 homozygous) at a frequency of 0.003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 625 of 30,782 chromosomes (freq: 0.02, increasing the likelihood this could be a low frequency benign variant), African in 18 of 24,036 chromosomes (freq: 0.0007), Other in 10 of 6468 chromosomes (freq: 0.002), Latino in 2 of 34,420 chromosomes (freq: 0.00006), European in 5 of 126,722 chromosomes (freq: 0.00004), and East Asian in 85 of 18,868 chromosomes (freq: 0.005), while it was not observed in the Ashkenazi Jewish and Finnish populations. The p.Thr483= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs at a non-highly conserved nucleotide 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.