Submissions for variant NM_000251.3(MSH2):c.1796T>C (p.Leu599Ser)

gnomAD frequency: 0.00001  dbSNP: rs747504492

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210095	SCV000266195	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000219087	SCV000273774	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	The p.L599S variant (also known as c.1796T>C), located in coding exon 12 of the MSH2 gene, results from a T to C substitution at nucleotide position 1796. The leucine at codon 599 is replaced by serine, 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 amino acid position is not 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.
GeneDx	RCV000520524	SCV000617005	uncertain significance	not provided	2023-10-17	criteria provided, single submitter	clinical testing	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; This variant is associated with the following publications: (PMID: 22874498, 21120944, 18822302, 33357406, 26845104, 34250417, 33848333)
Invitae	RCV000530644	SCV000625318	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000219087	SCV000684977	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-09	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 599 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 26845104). This variant has been identified in 3/251468 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.
Counsyl	RCV000662912	SCV000785841	uncertain significance	Lynch syndrome 1	2017-12-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000520524	SCV002048863	uncertain significance	not provided	2021-01-29	criteria provided, single submitter	clinical testing	The MSH2 c.1796T>C; p.Leu599Ser variant (rs747504492) is reported in the literature in an individual affected with breast cancer (Shirts 2016). This variant is found on only three chromosomes (3/251468 alleles) in the Genome Aggregation Database. The leucine at codon 599 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.613). However, due to limited information, the clinical significance of the p.Leu599Ser variant is uncertain at this time. References Shirts BH et al. Improving performance of multigene panels for genomic analysis of cancer predisposition. Genet Med. 2016 Oct;18(10):974-81.
Myriad Genetics, Inc.	RCV000662912	SCV004018275	likely benign	Lynch syndrome 1	2023-03-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330582	SCV004037608	uncertain significance	not specified	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1796T>C (p.Leu599Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) 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 1.2e-05 in 251468 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1796T>C has been reported in the literature as a VUS in settings of multigene panel testing among individuals undergoing cancer diagnostic testing (example, Shirts_2016, Pearlman_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Ollodart_2021). The following publications have been ascertained in the context of this evaluation (PMID: 33848333, 34250417, 26845104). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (LB, n=2; VUS, n=6). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000662912	SCV004196184	uncertain significance	Lynch syndrome 1	2023-10-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000520524	SCV004220958	uncertain significance	not provided	2023-07-05	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an affected individual with breast cancer (PMID: 26845104 (2016)). The frequency of this variant in the general population, 0.000026 (3/113752 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV004541299	SCV004793396	uncertain significance	MSH2-related disorder	2024-02-27	criteria provided, single submitter	clinical testing	The MSH2 c.1796T>C variant is predicted to result in the amino acid substitution p.Leu599Ser. This variant has been reported in an individual with breast cancer (Shirts et al. 2016. PubMed ID: 26845104). In vitro functional study did not support pathogenicity of this variant (Jia et al. 2021. PubMed ID: 33357406). This variant is reported in 0.0026% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as a variant of uncertain significance by majority of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/224577/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000210095	SCV004827366	uncertain significance	Lynch syndrome	2023-05-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 599 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 26845104). This variant has been identified in 3/251468 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.