rs876658211
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_StrongPP5
The NM_000251.3(MSH2):c.2680dup(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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
MSH2
NM_000251.3 frameshift
NM_000251.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.56
Genes affected
MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PVS1
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Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
PP5
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Variant 2-47482821-C-CA is Pathogenic according to our data. Variant chr2-47482821-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229809.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=2, Likely_pathogenic=5}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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MSH2 | NM_000251.3 | c.2680dup | p.Met894AsnfsTer5 | frameshift_variant | 16/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.2680dup | p.Met894AsnfsTer5 | frameshift_variant | 16/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152140Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251144Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135776
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461458Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727022
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152140Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74324
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:8Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 22, 2017 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Sep 10, 2014 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 13, 2023 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 03, 2023 | 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. - |
Lynch syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 14, 2024 | - - |
Lynch syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 24, 2020 | 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. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 22, 2023 | 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. - |
MSH2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 10, 2023 | 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
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