Submissions for variant NM_000251.3(MSH2):c.14C>T (p.Pro5Leu)

dbSNP: rs56170584

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160589	SCV000211184	uncertain significance	not provided	2016-03-22	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.14C>T at the cDNA level, p.Pro5Leu (P5L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Pro5Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Pro5Leu occurs at a position that is conserved across species and is located in the mismatch binding domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Pro5Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000559215	SCV000625274	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390391	SCV002701451	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-12	criteria provided, single submitter	clinical testing	The p.P5L variant (also known as c.14C>T), located in coding exon 1 of the MSH2 gene, results from a C to T substitution at nucleotide position 14. The proline at codon 5 is replaced by leucine, an amino acid with similar 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 01;108:163-175). This amino acid position is highly 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003325191	SCV004031219	uncertain significance	Lynch syndrome 1	2023-07-06	criteria provided, single submitter	clinical testing	The MSH2 c.14C>T (p.Pro5Leu) missense change has a maximum subpopulation frequency of 0.0020% 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 functionally neutral (PMID: 33357406). To our knowledge, this variant has not been reported in individuals with Lynch syndrome or constitutional mismatch repair deficiency. 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.
All of Us Research Program, National Institutes of Health	RCV003998472	SCV004825555	uncertain significance	Lynch syndrome	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 5 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 affected with esophageal squamous cell carcinoma (PMID: 31396961). This variant has been identified in 2/220468 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.