NM_000251.3:c.2680dupA
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_000251.3(MSH2):c.2680dupA(p.Met894AsnfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000496 in 1,613,598 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000251.3 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152140Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251144Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135776
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461458Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727022
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152140Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74324
ClinVar
Submissions by phenotype
not provided Pathogenic:4
- -
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. -
- -
- -
Lynch syndrome Pathogenic:2
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. -
The c.2680dup (p.Met894Asnfs*5) variant of the MSH2 gene is located on the last exon and is predicted to create an early stop codon. While this variant is not expected to result in nonsense mediated mRNA decay, it is predicted to disrupt the last 41 amino acids of the MSH2 protein. This variant has been reported in multiple individuals with colorectal cancer, Lynch syndrome, and ovarian cancer (PMID: 15713769, 22949379, 27601186, 28514183, 30077346, 30322717), including one individual with Lynch syndrome and a positive family history (PMID: 30077346). This variant has been identified in 3/251144 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Therefore, the c.2680dup (p.Met894Asnfs*5) variant of the MSH2 gene is classified as likely pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
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. -
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. -
Hereditary nonpolyposis colon cancer Pathogenic:1
Variant summary: MSH2 c.2680dupA (p.Met894AsnfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 251144 control chromosomes. c.2680dupA has been reported internally and in the literature in multiple individuals affected with clinical features of Hereditary Nonpolyposis Colorectal Cancer (example, Lagerstedt-Robinson_2016, Labcorp Genetics (formerly Invitae)). These data indicate that the variant is very likely to be associated with disease. 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, 15713769, 28514183, 30251116, 27601186, 35430768, 22949379). ClinVar contains an entry for this variant (Variation ID: 229809). Based on the evidence outlined above, the variant was classified as pathogenic. -
Lynch syndrome 1 Pathogenic:1
- -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
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 (internal data). For these reasons, this variant has been classified as Pathogenic. -
MSH2-related disorder Uncertain:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at