Submissions for variant NM_000251.3(MSH2):c.1600C>T (p.Arg534Cys)

gnomAD frequency: 0.00004  dbSNP: rs63750029

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524349	SCV000211917	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000410514	SCV000487881	uncertain significance	Lynch syndrome 1	2015-11-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000588411	SCV000567089	uncertain significance	not provided	2023-08-30	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; Observed in an individual reported to have HNPCC, but was also observed in a control population without personal or family history of colorectal cancer (Tournier et al., 2008; Arora et al., 2015); Mini-gene splicing assays have shown this variant to cause partial or complete skipping of exon 10 (Lastella et al., 2006; Tournier et al., 2008); This variant is associated with the following publications: (PMID: 16995940, 22290698, 18561205, 9490293, 26344056, 30798936, 18822302, 9774676, 21120944, 34426522, 31391288, 14526391, 29887214)
Ambry Genetics	RCV000491263	SCV000580434	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-02	criteria provided, single submitter	clinical testing	The p.R534C variant (also known as c.1600C>T), located in coding exon 10 of the MSH2 gene, results from a C to T substitution at nucleotide position 1600. The arginine at codon 534 is replaced by cysteine, an amino acid with highly dissimilar properties. A report in the literature suggests that this variant may have an effect on pre-mRNA splicing, by altering exonic splicing regulatory sequences. Additionally, this alteration was transfected into three different mammalian cell lines and a decrease in the exon inclusion levels in two of the three cell lines was seen (Lastella P et al. BMC Genomics. 2006 Sep;7:243). This alteration has also been reported to affect splicing by functional analysis using the ESE-dependent splicing assay (Tournier I et al. Hum. Mutat. 2008 Dec;29:1412-24). RNA studies have demonstrated this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). This variant was identified in a tumor with LOH of MSH2, but authors suggested classifying as VUS following multifactorial analysis (Shirts BH et al. Am J Hum Genet, 2018 07;103:19-29). This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health	RCV000491263	SCV000684952	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 534 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). Functional studies have shown conflicting results regarding the impact of this variant on mRNA splicing (PMID: 16995940, 18561205). This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 18561205), and an individual affected with an unspecified cancer (PMID: 31391288). This variant has also been reported in a healthy individual lacking personal or family history of colorectal cancer (PMID: 26344056). This variant has been identified in 2/282752 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175346	SCV000696220	uncertain significance	not specified	2021-12-17	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1600C>T (p.Arg534Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. A functional study showed a decrease in inclusion of exon 10 in an in-vitro mini-gene assay perfromed in several cell lines (Lastella_2006). The variant allele was found at a frequency of 4e-06 in 251364 control chromosomes. c.1600C>T has been reported in the literature in individuals affected with cancer and in controls (example, Gorlov_2003, Arora_2015, Li_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000076204	SCV000887412	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH2 NM_000251.2:c.1600C>T has a 76.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588411	SCV000889419	uncertain significance	not provided	2020-10-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410514	SCV004018386	likely benign	Lynch syndrome 1	2023-03-22	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].
Baylor Genetics	RCV000410514	SCV004196209	uncertain significance	Lynch syndrome 1	2023-10-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000076204	SCV004831780	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 534 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). Functional studies have shown conflicting results regarding the impact of this variant on mRNA splicing (PMID: 16995940, 18561205). This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 18561205), and an individual affected with an unspecified cancer (PMID: 31391288). This variant has also been reported in a healthy individual lacking personal or family history of colorectal cancer (PMID: 26344056). This variant has been identified in 2/282752 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.