ClinVar

Description

The p.Glu1163Val variant was identified in 4 of 2866 proband chromosomes (frequency: 0.001) from individuals or families with HNPCC and colorectal cancer), and was present in 5 of 642 control chromosomes (frequency: 0.008) from healthy individuals (Ali 2012, Limburg 2011, Nilbert 2009, Shin 2004, Yan 2007). The variant was also identified in dbSNP (ID: rs63750252 “With untested allele”, with a minor allele frequency of 0.0028 (14 of 5000 chromosomes in 1000 Genomes Project). This variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 143 of 121316 alleles (frequency: 0.001179) (including 119 of 8648:freq 0.01376 of East Asian chromosomes) and was not found in African and European (Finnish) populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Glu1163Val variant was identified in the Clinvar database and was classified as Benign by GeneDx, Ambry Genetics and Invitae; as Likely Benign by InSIGHT; as a variant of uncertain significance by Mayo Clinic Genetic Testing Laboratory and no classification was provided by ITMI. In UMD Colon Genes database the variant was identified 2X and classified as unknown. The variant co-occurred with a pathogenic MSH2 variant (c.518T>C, p.Leu173Pro). The InSIGHT database identified the variant 7X and classified it as likely not pathogenic and in the Zheijiang database the variant was identified 1X and classified unknown. In COSMIC database the variant was identified in a lymphoid tumour and in a culture. The p.Glu1163 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Valine variant may impact the protein, however this information is not predictive enough to assume pathogenicity. Additionally, in a Chinese population study the c.3488A>T was also found in the controls; the rate was approximately 3.65% (5/137) (Yan 2007). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.