Submissions for variant NM_000251.3(MSH2):c.19G>T (p.Glu7Ter)

dbSNP: rs375561490

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001014004	SCV001174655	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-25	criteria provided, single submitter	clinical testing	The p.E7* variant (also known as c.19G>T), located in coding exon 1 of the MSH2 gene, results from a G to T substitution at nucleotide position 19. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. The predicted stop codon occurs within the first 150 nucleotides of the MSH2 gene. This alteration may escape nonsense-mediated mRNA decay and/or be rescued by re-initiation through use of a downstream, in-frame AUG at codon 26 (Farrington SM et al. Am J Hum Genet, 1998 Sep;63:749-59; Kets CM et al. Eur J Hum Genet, 2009 Feb;17:159-64; Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). The exact functional effect of this alteration is unknown; however, MutS alpha complexes formed using recombinantly expressed wild type MSH6 and MSH2 with a deletion of the first 25 amino acids of the protein, demonstrated partially retained function in several biochemical assays that measured ATP binding, ATPase activity, mismatch binding, and sliding clamp formation (Cyr JL et al. Mol Carcinog, 2012 Aug;51:647-58). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001014004	SCV004356563	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-02	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 1 of the MSH2 gene, creating a premature translation stop signal. However this variant may escape nonsense-mediated mRNA decay due to secondary initiation at one of multiple downstream AUG start codons. Experimental studies have shown that a protein with a deletion of 25 amino acids of the N-terminal domain has been observed as partially functional (PMID: 21837758). An alternative MSH2 transcript (NM_001258281) lacking the first 66 amino acids of the primary transcript, is expressed at similar or higher levels in human tissues (https://gnomad.broadinstitute.org/). Premature stop codons located in close proximity to the canonical Met1 start codon often show a decrease in nonsense-mediated mRNA decay efficiency (PMID: 27618451). Missense variants impacting the start codon at Met1 are classified as VUS (ClinVar Variation ID: 90832, 90833, 230889). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. 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). The clinical impact of truncations in MSH2 prior to a secondary in-frame methionine at amino acid residue 26 is not fully understood at this time. Until further functional and clinical evidence is obtained, based on the evidence available this variant is classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV004588466	SCV005084213	pathogenic	Lynch syndrome 1	2024-06-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005093105	SCV005752395	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu7*) in the MSH2 gene. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 26 has the potential to rescue this variant. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 820493). Reports on variants that affect the MSH2 initiator codon, c.1A>C and c.1A>T, indicate that Met26 may serve as an alternate initiator codon (PMID: 21837758, 9718327, 18781192). An experimental study of a recombinant MSH2 protein lacking the first 25 amino acid residues has shown that the truncated protein remains partially functional (PMID: 21837758). The clinical significance of these findings is unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.