ClinVar Genomic variation as it relates to human health

The frequency of this variant in the general population, 0.00028 (6/21394 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. To the best of our knowledge, it has not been reported in individuals with an MSH2 related cancer. However, this variant has been described in the Exome Aggregation Consortium (ExAC) in publication (PMID: 26888055 (2016)) Based on the available information, we are unable to determine the clinical significance of this variant.

Variant summary: MSH2 c.-3G>C is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 1.9e-05 in 212752 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-3G>C has been reported in the literature in individuals affected with Colorectal Cancer (Yurgelun_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variant(s) have been reported (MLH1 c.2070_2071insTT, p.I691Lfs), providing supporting evidence for a benign role (Yurgelun_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 127624). Based on the evidence outlined above, the variant was classified as uncertain significance.

Nucleotide substitution has no predicted effect on splicing and is not conserved across species; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533)

This variant is located in the 5' untranslated region of the MSH2 gene. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 7/244138 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This variant occurs in a non-coding region of the MSH2 gene. It does not change the encoded amino acid sequence of the MSH2 protein. This variant is present in population databases (rs587779960, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 127624). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This variant is considered likely benign. 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].

This variant is located in the 5' untranslated region of the MSH2 gene. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 7/244138 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The c.-3G>C variant is located in the 5' untranslated region (5’ UTR) of the MSH2 gene. This variant results from a G to C substitution 3 bases upstream from the first translated codon. This nucleotide position is not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The MSH2 c.-3G>C variant was not identified in the literature nor was it identified in the COGR, Cosmic, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or InSiGHT Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs587779960 as "With Uncertain significance allele") and ClinVar (5x as uncertain significance by GeneDx, Ambry Genetics, Counsyl, Color Genomics, and Integrated Genetics/Laboratory Corporation of America). The variant was identified in control databases in 8 of 238158 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 7 of 20486 chromosomes (freq: 0.0003) and Latino in 1 of 30410 chromosomes (freq: 0.00003); it was not observed in the Other, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.-3G>C variant is located in the kozak consensus sequence and typically a purine (adenine or guanine) is always observed at this position, increasing the likelihood this variant may have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

The MSH2 c.-3G>C variant is located in the 5' untranslated region. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127624/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.