Submissions for variant NM_000251.3(MSH2):c.942+2T>A

gnomAD frequency: 0.00101  dbSNP: rs587779195

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491819	SCV000580467	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-12	criteria provided, single submitter	clinical testing	The c.942+2T>A intronic pathogenic mutation results from a T to A substitution two nucleotides after coding exon 5 in the MSH2 gene. This mutation has been reported in multiple individuals with Lynch syndrome-associate cancers who met Amsterdam I or II criteria or Bethesda Guidelines and whose tumors were MSI-H and showed absence of MSH2 on immunohistochemistry (de Lellis L at al. PLoS ONE 2013;8(11):e81194; Castillejo MI et al. eJIFCC Volume 27 no 1; February 2016). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000491819	SCV001357860	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-03-23	criteria provided, single submitter	clinical testing	This variant causes a T to A nucleotide substitution at the +2 position of intron 5 of the MSH2 gene. This variant is found adjacent to a poly-adenosine sequence, where the precise number of adenosine is difficult to determine via conventional sequencing technologies. Therefore, this variant may be reported by external laboratories as a deletion encompassing the +2T and varying number of adenosine, e.g. c.942+2del (ClinVar variation ID 91250) and c.942+2_942+6del (ClinVar variation ID 237416). All such variants are predicted to have the same splicing impact. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to disrupt the DNA binding domain of the MSH2 protein. This variant has been reported in an individual affected with Lynch syndrome–associated cancer and/or polyps (PMID: 25980754). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001229248	SCV001401688	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-10-15	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 24278394, 25980754). ClinVar contains an entry for this variant (Variation ID: 428474). Studies have shown that disruption of this splice site results in skipping of exon 5, but is expected to preserve the integrity of the reading-frame (internal data). This variant disrupts a region of the MSH2 protein in which other variant(s) (p.Leu310) have been determined to be pathogenic (internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800711	SCV002047062	pathogenic	not provided	2021-05-10	criteria provided, single submitter	clinical testing	This variant is located in a canonical splice-donor site and interferes with normal MSH2 mRNA splicing. The variant has been reported in individuals with Lynch syndrome-associated cancer and/or polyps in the published literature (PMIDs: 21239990 (2011), 24278394 (2013), 25980754 (2015), and 33630411 (2021)). In addition, tumors of individuals with this variant were MSI-H and showed absence of MSH2 protein on immunohistochemistry (PMIDs: 24278394 (2013) and 33630411 (2021)). Therefore, the variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003449349	SCV004187988	pathogenic	Lynch syndrome 1	2023-07-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. Functional studies indicate this variant impacts protein function [PMID: 8062247].
Baylor Genetics	RCV003449349	SCV004196944	likely pathogenic	Lynch syndrome 1	2021-01-15	criteria provided, single submitter	clinical testing