ClinVar

Description

The MSH6 p.Pro42Ser variant was identified in 3 of 3168 proband chromosomes (frequency: 0.0009) from individuals or families with Lynch Syndrome (Hampel 2005, Yurgelun 2015, Carneiro da Silva 2015 26437257). The variant was identified in dbSNP (rs34014629) as “with uncertain significance allele” and ClinVar (classified as likely benign by Invitae, Ambry Genetics, Color and 2 other submitters; and as uncertain significance by InSiGHT and Counsyl). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 40 of 258,896 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 39 of 21,150 chromosomes (freq: 0.002, increasing the likelihood this could be a low frequency benign variant) and Latino in 1 of 34,080 chromosomes (freq: 0.00003), while it was not observed in the Ashkenazi Jewish, East Asian, Finnish, European, Other or South Asian populations. The p.Pro42 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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, 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.