ClinVar Genomic variation as it relates to human health

This missense variant replaces asparagine with isoleucine at codon 583 in 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 individuals affected with colorectal cancer (PMID: 11376800, 19526325, 33359728). In a large breast cancer case-control study, this variant has been reported in 1/60466 cases, 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/250860 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 p.N583I variant (also known as c.1748A>T), located in coding exon 11 of the MSH2 gene, results from an A to T substitution at nucleotide position 1748. The asparagine at codon 583 is replaced by isoleucine, an amino acid with dissimilar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This alteration was identified in an individual diagnosed with colorectal cancer (Dharwadkar P et al. Clin Gastroenterol Hepatol, 2022 Feb;20:353-361.e3). This alteration was also detected in a cohort of unrelated Brazilian individuals diagnosed with breast cancer (Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The MSH2 c.1748A>T; p.Asn583Ile variant (rs201118107) is reported in the literature in the germline of individuals with colorectal cancer (Berginc 2009, Potocnik 2001). This variant is also reported in the ClinVar database (Variation ID: 229675). It is only observed on 3 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The asparagine at codon 583 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Berginc G et al. Screening for germline mutations of MLH1, MSH2, MSH6 and PMS2 genes in Slovenian colorectal cancer patients: implications for a population specific detection strategy of Lynch syndrome. Fam Cancer. 2009;8(4):421-9. Potocnik U et al. Causes of microsatellite instability in colorectal tumors: implications for hereditary non-polyposis colorectal cancer screening. Cancer Genet Cytogenet. 2001 Apr 15;126(2):85-96.

DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1748A>T, in exon 11 that results in an amino acid change, p.Asn583Ile. This sequence change has been described in the gnomAD database in three individuals (dbSNP rs201118107). The p.Asn583Ile change has been described in several individuals with colorectal cancer (PMIDs: 11376800, 19526325). The p.Asn583Ile change affects a moderately conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Asn583Ile substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Asn583Ile change remains unknown at this time.

The MSH2 c.1748A>T (p.Asn583Ile) missense change has a maximum subpopulation frequency of 0.0029% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, however a functional assay using a massively parallel screen in human cells indicated that this variant is neutral (PMID: 33357406). This variant has been reported in individuals with colorectal cancer (PMID: 11376800, 19526325). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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.

This missense variant replaces asparagine with isoleucine at codon 583 in 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 individuals affected with colorectal cancer (PMID: 11376800, 19526325, 33359728). In a large breast cancer case-control study, this variant has been reported in 1/60466 cases, 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/250860 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 p.Asn583Ile variant was identified in 2 of 1876 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer (Berginc 2009, Potočnik 2001). The variant was also identified in dbSNP (ID: rs201118107) as "With Uncertain significance allele" and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, Counsyl and Color). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 3 of 245916 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33576 chromosomes (freq: 0.00003) and European in 2 of 111446 chromosomes (freq: 0.00002); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asn583 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.