ClinVar Genomic variation as it relates to human health

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30798936)

This alteration is classified as likely 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.

Variant summary: MSH2 c.2354A>G (p.His785Arg) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251450 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2354A>G in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This missense variant replaces histidine with arginine at codon 785 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 two individuals affected with Lynch syndrome-associated cancer (ClinVar SCV000864156.1; Color internal data). In a large breast cancer case-control study, this variant was reported in one affected individual and two unaffected controls (PMID: 33471991). This variant has been identified in 2/282842 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.

Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 77 year old female diagnosed with colon cancer at age 74. Family history of colorectal cancer and/or polyps. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.

The MSH2 c.2354A>G, p.His785Arg variant (rs200252727), to our knowledge, has not been reported in the medical literature; however, this variant is listed in the ClinVar database (Variation ID: 188316). This variant is found in the general population with an overall allele frequency of 0.0007% (2/282,842 alleles) in the Genome Aggregation Database. The histidine at codon 785 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.973). A different variant effecting this codon (p.His785Pro) has was identified in a 28 year old man with a diagnosis of colorectal cancer (Chubb 2015). However, based on the available information, the clinical significance of the p.His785Arg variant is uncertain. References: Chubb D et al. Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing. J Clin Oncol. 2015 Feb 10;33(5):426-32.

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 785 of the MSH2 protein (p.His785Arg). This variant is present in population databases (rs200252727, gnomAD 0.002%). 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: 188316). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. 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 missense variant replaces histidine with arginine at codon 785 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). However, a functional study has reported that this variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). This variant has been reported in two individuals affected with Lynch syndrome-associated cancer (ClinVar variation ID 188316, Color internal data), and in an individual affected with Muir-Torre syndrome (http://www.umd.be/). This variant also has been reported in a breast cancer case-study, where it has been detected in 1 breast cancer case and 2 unaffected controls (PMID: 33471991; LOVD individual #00352263, 00357039). This variant has been identified in 2/282842 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 MSH2 c.2354A>G variant is predicted to result in the amino acid substitution p.His785Arg. This variant has been reported in an individual with Muirr-Torre sydrome, an individual with colorectal cancer over age 70, and an individual with breast cancer in addition to two controls (Joly et al. 2015. PubMed ID: 25504677; Ollodart et al. 2021. PubMed ID: 33848333; Dorling et al. 2021. PubMed ID: 33471991). This variant is reported in 0.0015% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting classifications listed in ClinVar ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/188316/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.