ClinVar Genomic variation as it relates to human health

Variant summary: The MSH6 c.3647-6T>A variant involves the alteration of a non-conserved intronic nucleotide with 4/5 splice prediction tools predict no significant impact on normal splicing, which a reputable database reports in vitro and ex vivo analyses that support these predictions. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 47/120200 (1/2557), predominantly in the African cohort, 42/10262 (1/244), which exceeds the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7037. Therefore, suggesting this is likely a benign polymorphism found primarily in population(s) of African origin. The variant of interest has been reported by multiple clinical diagnostic laboratories/databases with conflicting classifications "Benign/Likely Benign/Uncertain Significance." Therefore, taking all available lines of evidence into consideration, the variant of interest has been 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

The MSH6 c.3647-6T>A variant was not identified in the literature. The variant was identified in dbSNP (ID: rs182871847) as "With Likely benign, other allele", ClinVar (classified as benign by Invitae and two clinical laboratories; as likely benign by GeneDx, Color and Councyl; as uncertain significance by two submitters), and in UMD-LSDB (1x as likely neutral). The variant was identified in control databases in 117 of 276924 chromosomes at a frequency of 0.0004 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: African in 107 of 24034 chromosomes (freq: 0.005), Other in 1 of 6444 chromosomes (freq: 0.0002), Latino in 9 of 34364 chromosomes (freq: 0.0003), while the variant was not observed in the European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The c.3647-6T>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% 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.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).