ClinVar

Description

The MSH6 p.Thr757= variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (rs142172006) as “with likely benign, uncertain significance allele” and ClinVar (classified as likely benign by Invitae, Ambry Genetics, Color and 2 other submitters; and as uncertain significance by Integrated Genetics). The variant was identified in control databases in 7 of 276,782 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24,022 chromosomes (freq: 0.00004) and European in 6 of 126,318 chromosomes (freq: 0.00005); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish or South Asian populations. In our laboratory, the variant was identified as co-occurring with a pathogenic MSH6 variant (c.1883G>A, p.Trp628*). The p.Thr757= 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, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.