Submissions for variant NM_000251.3(MSH2):c.2680dup (p.Met894fs)

dbSNP: rs876658211

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214664	SCV000273149	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-13	criteria provided, single submitter	clinical testing	The c.2680dupA pathogenic mutation, located in coding exon 16 of the MSH2 gene, results from a duplication of one nucleotide at position c.2680 resulting in a translational frameshift with a predicted alternate stop codon (p.M894Nfs*5). This alteration occurs at the 3' terminus of the MSH2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 41 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant has been detected in multiple individuals diagnosed with colorectal cancer that demonstrated either high microsatellite instability (MSI-H) or absent MSH2 and/or MSH6 staining by immunohistochemistry (IHC) (Ambry internal data; Casey G et al. JAMA 2005 Feb; 293(7):799-809). As such, this alteration is interpreted as a disease-causing mutation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000614715	SCV000731411	likely pathogenic	Lynch syndrome	2020-07-24	criteria provided, single submitter	clinical testing	The p.Met894AsnfsX5 variant in MSH2 has been reported in at least 2 individuals with Lynch syndrome associated cancers (Casey 2005 PMID: 15713769, Lagerstedt-Robinson 2016 PMID: 27601186, Carter 2018 PMID: 30322717). In addition, tumors sampled from 1 of these individuals lacked MSH2 and MSH6 expression. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 229809) and has been identified in 0.003% (3/113586) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 894 and leads to a premature termination codon 5 amino acids downstream. This termination codon occurs within the last exon and is therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing ~4% of the coding region, with 36 amino acids removed. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1_Moderate, PM2, PS4_Supporting, PS3_Moderate.
GeneDx	RCV000657245	SCV000778975	likely pathogenic	not provided	2017-08-22	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in MSH2 is denoted c.2680dupA at the cDNA level and p.Met894AsnfsX5 (M894NfsX5) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ACAA[dupA]TGCC. The duplication causes a frameshift which changes a Methionine to an Asparagine at codon 894, and creates a premature stop codon at position 5 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. MSH2 c.2680dupA has been reported in individuals with Lynch syndrome, and mismatch repair immunohistochemistry (MMR IHC) data available on a tumor showed loss of MSH2 and MSH6 in at least one carrier (Casey 2005, Lagerstedt-Robinson 2016). Based on the currently available information, we consider this duplication to be a likely pathogenic variant.
Color Diagnostics, LLC DBA Color Health	RCV000214664	SCV000908332	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-03	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 16 of the MSH2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with endometrial, ovarian, and colorectal cancer (PMID: 15713769, 30077346, 30322717, PMID: 35430768; ClinVar SCV000273149.7) and in families with suspected Lynch syndrome (PMID: 27601186). A couple of the individuals affected with colorectal cancer had tumors with either loss of MSH2 and MSH6 protein via immunohistochemistry and/or high microsatellite instability (PMID: 15713769; ClinVar SCV000273149.7). This variant has been identified in 3/251144 chromosomes 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.
Invitae	RCV000810344	SCV000950540	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met894Asnfs*5) in the MSH2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the MSH2 protein. This variant is present in population databases (rs756190190, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with clinical features of Lynch syndrome (PMID: 27601186, 28514183, 30322717; external communication). ClinVar contains an entry for this variant (Variation ID: 229809). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000657245	SCV001449568	pathogenic	not provided	2014-09-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235138	SCV003934379	uncertain significance	not specified	2023-05-22	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2680dupA (p.Met894AsnfsX5) located in the last exon results in a premature termination codon, predicted to cause a truncation of the encoded protein. The variant allele was found at a frequency of 1.2e-05 in 251144 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2680dupA has been reported in the literature in individuals reportedly affected with features of Lynch Syndrome and in settings of multigene panel analysis among referral laboratory cohorts (example, Carter_2018, Lagerstedt_Robinson_2016, Thompson_2013, Casey_2005, Espenschied_2017, Henriksson_2019, Svensson_2022). At-least one of these studies reported its presence with IHC findings reporting loss of MSH2 and MSH6 although the MSI status is not clearly specified (Casey_2005). Additionally, some studies are likely to represent a cohort overlap (Lagerstedt_Robinson_2016, Henriksson_2019, Svensson_2022). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30322717, 27601186, 22949379, 15713769, 28514183, 30251116, 35430768). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 . Multiple laboratories reported the variant with conflicting assessments: VUS (n=2), Likely Pathogenic (n=2) and Pathogenic (n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV003462410	SCV004196277	likely pathogenic	Lynch syndrome 1	2023-09-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541345	SCV004790971	uncertain significance	MSH2-related disorder	2023-11-10	criteria provided, single submitter	clinical testing	The MSH2 c.2680dupA variant is predicted to result in a frameshift and premature protein termination (p.Met894Asnfs*5). This variant has been reported in at least five individuals with Lynch syndrome cancers and an additional individual undergoing Lynch syndrome genetic testing (Table 6. Casey et al. 2005. PubMed ID: 15713769; Table S1, Carter et al. 2018. PubMed ID: 30322717; Table 1, Lagerstedt-Robinson et al. 2016. PubMed ID: 27601186; Table A2, Espenschied et al. 2017. PubMed ID: 28514183; Sup. Material 2, Svensson et al. 2022. PubMed ID: 35430768; Case 1, Bujassoum et al. 2018. J Cancer Sci Ther. 10:9. DOI: 10.4172/1948-5956.1000550). It has also been reported in a mismatch repair deficient Lynch syndrome tumor specimen (Table S2, Henriksson et al. 2019. PubMed ID: 30251116). This variant is reported in 3 of ~251,000 alleles in gnomAD (https://gnomad.broadinstitute.org/variant/2-47709960-C-CA?dataset=gnomad_r2_1). It has conflicting classifications listed in ClinVar ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/229809/). This variant resides in the final exon of this gene, and it is unclear if the resulting mRNA would undergo nonsense-mediated decay. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.