rs587781278
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM4BP6
The NM_000251.3(MSH2):c.2576_2584del(p.Glu859_Gln861del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G858G) has been classified as Likely benign.
Frequency
Consequence
NM_000251.3 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.2576_2584del | p.Glu859_Gln861del | inframe_deletion | 15/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.2576_2584del | p.Glu859_Gln861del | inframe_deletion | 15/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152156Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251448Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135896
GnomAD4 exome AF: 0.000103 AC: 150AN: 1461832Hom.: 0 AF XY: 0.0000908 AC XY: 66AN XY: 727220
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152156Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74338
ClinVar
Submissions by phenotype
not specified Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 report - no effect on protein expression; ClinVar: 2 VUS - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 07, 2020 | Variant summary: MSH2 c.2576_2584delAATCGCAAG (p.Glu859_Gln861del) results in an in-frame deletion that is predicted to remove three amino acids from helix-turn-helix domain in the encoded MSH2 protein. The variant allele was found at a frequency of 2e-05 in 251448 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2576_2584delAATCGCAAG has been reported in the literature in individuals affected with colon cancer and endometrial carcinoma (Plevova_2004, Casey_2005, Poynter_2008, Ring_2016). However, immunohistochemical analysis showed that there is no effect on expression of MLH1, MSH2 and MSH6 proteins (Plevova_2004, Casey_2005, Poynter_2008). 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. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (7x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Uncertain significance, no assertion criteria provided | research | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 05, 2019 | - - |
Lynch syndrome 1 Uncertain:4Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Nov 24, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | Mar 24, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 03, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 20, 2023 | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. - |
not provided Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 30, 2023 | This variant results in the in-frame deletion of three amino acids from the MSH2 protein, and has been reported in the published literature in individuals with endometrial cancer (PMID: 27443514 (2016)), and colorectal cancer in which the tumors were immunohistochemically positive for MSH2 expression (PMIDs: 18990764 (2008), 15713769 (2005), 15254659 (2004)). In a family study, this variant was characterized as being likely benign based on multifactorial analysis, and was identified in a cancer-free 72 year-old individual as well as in family members with colon polyps and pancreatic cancer (PMID: 30374176 (2019)). The frequency of this variant in the general population, 0.000039 (5/129166 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2023 | In-frame deletion of 3 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Observed in individuals with endometrial or colorectal cancer (Plevova et al., 2004; Casey et al., 2005; Ring et al., 2016); Located in the critical helix-turn-helix domain (Lutzen et al., 2008; Kansikas et al., 2011); This variant is associated with the following publications: (PMID: 15713769, 18822302, 27720647, 27443514, 30374176, 18990764, 15254659, 24194902, 21120944) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | MSH2: PM4, BP4 - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 05, 2023 | This variant causes an in-frame deletion of three amino acids (Glu859-Gln861) in exon 15 of the MSH2 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in at least one individual each affected with endometrial and early onset colorectal cancer, in the latter case the tumor sample showed the presence of MSH2 by immunohistochemistry (PMID: 15713769, 18990764, 27443514). A multifactorial analysis based on family study data has reported this variant as likely benign due in part to cosegregation likelihood ratio of 0.2554 from one observed family (PMID: 30374176). This variant has been identified in 6/282854 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 17, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 21, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Lynch syndrome Benign:1
Likely benign, criteria provided, single submitter | research | University of Washington Department of Laboratory Medicine, University of Washington | Apr 01, 2018 | The MSH2 gene variant designated as NM_000251.2:c.2576_2584delAATCGCAAG (p.E859_Q861del) is classified as likely benign. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 0.256:1 favoring a benign classification (Thompson et al., 2003, PMID:2900794). Data from a large reference laboratory cohort indicates that this variant was identified in many more individuals without MSH2 associated cancers than individuals affected with MSH2 associated cancers. In addition, the genomic position of this variant is not highly conserved, which also supports benign classification. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MSH2 function or cause an increased risk of Lynch syndrome associated cancers. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at