ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.458C>T (p.Ser153Phe)

gnomAD frequency: 0.00001  dbSNP: rs766349734
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001022744 SCV001184514 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-01 criteria provided, single submitter clinical testing The p.S153F variant (also known as c.458C>T), located in coding exon 3 of the MSH2 gene, results from a C to T substitution at nucleotide position 458. The serine at codon 153 is replaced by phenylalanine, an amino acid with highly 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 amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001066450 SCV001231461 benign Hereditary nonpolyposis colorectal neoplasms 2023-10-09 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004004631 SCV004824512 uncertain significance Lynch syndrome 2023-06-26 criteria provided, single submitter clinical testing This missense variant replaces serine with phenylalanine at codon 153 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251454 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.

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