ClinVar Genomic variation as it relates to human health

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP5. This variant was detected in homozygous state.

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

Variant summary: MSH2 c.274C>G (p.Leu92Val) results in a conservative amino acid change located in the N-terminal domain (IPR007695) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251214 control chromosomes, predominantly at a frequency of 0.00026 within the South Asian subpopulation in the gnomAD database. This subpopulation frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in MSH2 causing Lynch Syndrome (0.00057), allowing no clear conclusion about variant significance. The variant, c.274C>G, has been reported in the literature in heterozygous state in individuals affected with Lynch Syndrome related tumors (Betz_2010, Yurgelun_2017), and unspecified tumor phenotype (Bhai_2021). However, co-occurrences with other pathogenic variants have been reported (MSH6 c.2653A>T, p.Lys885X in the UMD database; and MSH2 exons 1-6 deletion in Yurgelun_2017), providing supporting evidence for a benign role. In addition, the variant was also reported in homozygous state in a patient with constitutional mismatch repair deficiency syndrome (Taeubner_2018, Brozou_2018, Gallon_2019), however the patient also carried a homozygous MSH6 variant, and functional studies performed on patient derived samples suggested that the MSH2 variant was unlikely to be disease causing in this patient (Taeubner_2018, Gallon_2019). The following publications have been ascertained in the context of this evaluation (PMID: 19669161, 29302048, 28929227, 30740824, 34326862, 28135145). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and reported the variant with conflicting assessments, i.e. likely pathogenic (n=1), VUS (n=6), likely benign (n=2) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.

A heterozygous missense variation in exon 2 of the MSH2 gene that results in the amino acid substitution of Valine for Leucine at codon 92 was detected. The observed variant c.274C>G (p.Leu92Val) has not been reported in the 1000 genomes and has a minor allele frequency of 0.005% in the gnomAD database. The observed variation has previously been reported in an individual with family history of Lynch syndrome (Betz B et al. 2010) and it lies in the MutS domain I of the MSH2_HUMAN protein. The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2 tools. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance.

This missense variant replaces leucine with valine at codon 92 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual with personal and/or family history of Lynch syndrome-associated cancers (PMID: 19669161). This variant has also been reported in the homozygous state in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 28929227, 29302048). However, the individual was found to also have a homozygous variant in the MSH6 gene. The primary cause of the disease is not clear. This variant has been identified in 15/251214 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 missense variant replaces leucine with valine at codon 92 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual with personal and/or family history of Lynch syndrome-associated cancers (PMID: 19669161). This variant has also been reported in the homozygous state in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 28929227, 29302048). However, the individual was found to also have a homozygous variant in the MSH6 gene. The primary cause of the disease is not clear. This variant has been identified in 15/251214 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 is associated with the following publications: (PMID: 19669161, 26333163, 28135145)

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

The p.Leu92Val variant has been reported in the literature from an individual in the German HNPCC consortium in a study that examined several in-silico programs (Betz 2010); "no changes" were predicted for this variant. The variant was also identified in the InSight, Medical center Groningen and Memorial University MMR databases. This residue is conserved in mammals but not in lower organisms and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein, but this information is not very predictive of pathogenicity. This variant is identified by our laboratory in one individual with a co-occuring pathogenic variant, increasing the likelihood this variant does not have clinical significance. In summary, the clinical significance of this variant cannot be determined with certainty, although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.