chr2-47799457-A-G
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_000179.3(MSH6):c.1474A>G(p.Met492Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M492T) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )
Consequence
MSH6
NM_000179.3 missense
NM_000179.3 missense
Scores
3
14
2
Clinical Significance
Conservation
PhyloP100: 9.29
Genes affected
MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]
FBXO11 (HGNC:13590): (F-box protein 11) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
BP6
Variant 2-47799457-A-G is Benign according to our data. Variant chr2-47799457-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89195.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=9}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| MSH6 | NM_000179.3 | c.1474A>G | p.Met492Val | missense_variant | 4/10 | ENST00000234420.11 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MSH6 | ENST00000234420.11 | c.1474A>G | p.Met492Val | missense_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes 0.0000789 AC: 12AN: 152176Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000796 AC: 20AN: 251172Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135734
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GnomAD4 exome AF: 0.000104 AC: 152AN: 1461870Hom.: 0 Cov.: 34 AF XY: 0.000111 AC XY: 81AN XY: 727230
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GnomAD4 genome 0.0000789 AC: 12AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74346
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 26, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest no damaging effect: mismatch repair activity comparable to wild-type (PMID: 22102614); Identified in individuals with Lynch syndrome-associated and other cancers (PMID: 12658575, 18566915, 22495361, 23047549, 28767289, 29684080, 35430768); This variant is associated with the following publications: (PMID: 23047549, 26333163, 23621914, 12658575, 18566915, 22495361, 28767289, 29684080, 29899834, 31391288, 31422818, 33471991, 17531815, 21120944, 36793599, 36865205, 35430768, 22102614) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 15, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 22, 2023 | In the published literature, this variant has been identified in individuals with Lynch syndrome (PMID: 22495361 (2012), 18566915 (2009), 12658575 (2003)), ovarian cancer (PMID: 23047549 (2012)), and pancreatic cancer (PMID: 28767289 (2017)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as unaffected individuals (see LOVD (http://databases.lovd.nl/shared/genes/MSH6) and PMID: 33471991 (2021)). An in vitro functional study has reported that this variant causes a slight reduction in mismatch repair activity (PMID: 22102614 (2012)). The frequency of this variant in the general population, 0.00048 (12/25118 chromosomes in European (Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
not specified Uncertain:2Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 27, 2023 | Variant summary: MSH6 c.1474A>G (p.Met492Val) results in a conservative amino acid change located in the N-terminal domain (IPR007695) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 1,607,050 control chromosomes, predominantly at a frequency of 0.00058 within the Finnish subpopulation in the gnomAD database (v4.0 dataset). The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism. c.1474A>G has been reported in the literature in individuals affected with suspected Lynch Syndrome (e.g. Wagner_2003, Nilbert_2009, Okkels_2012, ), and ovarian cancer (Pal_2012), without strong evidence for causality (lacking co-segregation data), but was also found in controls (Dorling_2021). At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated in an in vitro assay that variant has similar MMR activity to the WT (Drost_2011). A recent analysis found no supportive evidence for a highly penetrant disease association for this variant (Pan_2023). The following publications have been ascertained in the context of this evaluation (PMID: 12658575, 18566915, 22102614, 23047549, 22495361, 33471991, 36793599). Ten other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=8), or likely benign (n=8). Based on the evidence outlined above, the variant was classified as likely benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 30, 2016 | The p.Met492Val variant in MSH6 has been reported in 4 individuals with Lynch sy ndrome-related cancers (Wagner 2003, Okkels 2012, Pal 2012). In vitro functional studies provide some evidence that the p.Met492Val variant may not impact prote in function (Drost 2012). However, these types of assays may not accurately repr esent biological function. This variant has been identified in 3/6610 Finnish ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs61754783). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In addit ion, this variant was classified as a Variant of Uncertain Significance on Sep 5 , 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107859.2). In summary, the clinical significance of the p.Met492Val variant is uncertain. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 08, 2024 | The p.M492V variant (also known as c.1474A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1474. The methionine at codon 492 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported as a variant of unknown significance in multiple individuals, including one family from the Danish HNPCC-registry (Nilbert M et al. Fam. Cancer. 2009 Jun;8:75-83), one family meeting Amsterdam criteria (Wagner A et al. Am. J. Hum. Genet. 2003 May;72:1088-100), two unrelated individuals from HNPCC families with colon tumors demonstrating normal MSH6 expression on IHC studies (Okkels H et al. Appl. Immunohistochem. Mol. Morphol. 2012 Oct;20:470-7), and a patient diagnosed with a pancreatic neuroendocrine tumor at age 57 (Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390). In addition, one functional study reported this variant to be proficient in in vitro mismatch repair (MMR) activity (Drost M et al. Hum. Mutat. 2012 Mar;33:488-94). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 06, 2023 | This missense variant replaces methionine with valine at codon 492 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not affect MSH6 mismatch repair activity (PMID: 22102614). This variant has been reported in individuals with Lynch syndrome (PMID: 12658575, 18566915, 22495361), in an individual affected with ovarian cancer (PMID: 23047549), and in an individual affected with pancreatic neuroendocrine tumor (PMID: 28767289). This variant occurs at an elevated frequency in the general population and has been identified in 23/282572 chromosomes 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. - |
Carcinoma of colon Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Met492Val variant was identified in 2 of 2234 proband chromosomes (frequency: 0.001) from families with Lynch syndrome (Nilbert 2009, Wagner 2003); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs61754783) “With Uncertain significance allele”, HGMD, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, ClinVar database (classified as having uncertain significance by the InSiGHT expert review panel), and UMD (1X as an unclassified variant). An in vitro functional study by Drost (2011) demonstrated that the variant had similar mismatch repair efficiency to wild type MSH6, and an in silico study analyzing structural properties suggests that the variant has no impact on the MSH6 protein (Terui 2013).The p.Met492 residue is conserved in mammals but not across all lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. - |
Lynch syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 15, 2023 | This missense variant replaces methionine with valine at codon 492 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not affect MSH6 mismatch repair activity (PMID: 22102614). This variant has been reported in individuals with Lynch syndrome (PMID: 12658575, 18566915, 22495361), in an individual affected with ovarian cancer (PMID: 23047549), and in an individual affected with pancreatic neuroendocrine tumor (PMID: 28767289). This variant occurs at an elevated frequency in the general population and has been identified in 23/282572 chromosomes 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. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;.;D;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;.;L;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;D;D;.;D
REVEL
Pathogenic
Sift
Uncertain
.;D;D;.;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
0.77
.;.;P;.;.
Vest4
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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gMVP
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at