chr2-47799805-A-G
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000179.3(MSH6):c.1822A>G(p.Ile608Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000065 ( 0 hom. )
Consequence
MSH6
NM_000179.3 missense
NM_000179.3 missense
Scores
1
18
Clinical Significance
Conservation
PhyloP100: 0.970
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 -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.079576164).
BP6
Variant 2-47799805-A-G is Benign according to our data. Variant chr2-47799805-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182626.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MSH6 | NM_000179.3 | c.1822A>G | p.Ile608Val | missense_variant | 4/10 | ENST00000234420.11 | NP_000170.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MSH6 | ENST00000234420.11 | c.1822A>G | p.Ile608Val | missense_variant | 4/10 | 1 | NM_000179.3 | ENSP00000234420.5 |
Frequencies
GnomAD3 genomes 0.0000328 AC: 5AN: 152244Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250564Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135720
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GnomAD4 exome AF: 0.0000650 AC: 95AN: 1461882Hom.: 0 Cov.: 34 AF XY: 0.0000619 AC XY: 45AN XY: 727240
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GnomAD4 genome 0.0000328 AC: 5AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74376
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 08, 2024 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, melanoma, or a Lynch-syndrome related cancer and/or polyps, as well as in unaffected control groups (PMID: 30374176, 25980754, 33471991, 30267214, 29684080); This variant is associated with the following publications: (PMID: 23621914, 30374176, 25980754, 30267214, 33471991, 29684080, 17531815, 21120944) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 05, 2024 | The MSH6 c.1822A>G (p.Ile608Val) variant has been reported in the published literature in an individual with a Lynch Syndrome associated cancer and/or polyps (PMID: 25980754 (2015)). In a large-scale breast cancer association study, the variant was observed in an individual with breast cancer as well as in a reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). The frequency of this variant in the general population, 0.000054 (7/128860 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 01, 2024 | BP4 - |
Hereditary cancer-predisposing syndrome Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 11, 2024 | The p.I608V variant (also known as c.1822A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1822. The isoleucine at codon 608 is replaced by valine, an amino acid with highly similar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). In another study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). Additionally, in a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 25, 2023 | This missense variant replaces isoleucine with valine at codon 608 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has also been identified in 8/281964 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 | Sep 16, 2021 | - - |
Lynch syndrome Uncertain:2Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | This missense variant replaces isoleucine with valine at codon 608 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has also been identified in 8/281964 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. - |
| Likely benign, criteria provided, single submitter | research | University of Washington Department of Laboratory Medicine, University of Washington | Apr 30, 2018 | The MSH6 variant designated as NM_000179.2:c.1822A>G (p.Ile608Val) is classified as likely benign. Based on in-silico scores the variant has a prior probability of pathogenicity of 10% (Thompson et al., 2013, PMID:22949379). Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303). Analysis of one family gave a likelihood ratio of 0.34 to 1 that this allele explains cancer in the family (Thompson, et al., 2003, PMID:2900794). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MSH6 function or modify cancer risk for Lynch syndrome. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. - |
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH6 p.Ile608Val variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch syndrome-related cancer and/or colorectal polyps (Yurgelun 2015). In this study, the variant co-occurred with a pathogenic MUTYH variant (c.734G>A, p.Arg245His) in the affected individual. The variant was also identified in dbSNP (ID: rs201613780) as “With Uncertain significance allele”, ClinVar (classified as likely benign by University of Washington Dept. of Laboratory Medicine and as uncertain significance by GeneDx, Invitae, Ambry Genetics, Color and Integrated Genetics/Laboratory Corp. of America). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 8 of 276892 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017); observed in the following populations: European Non-Finnish in 7 of 126468 chromosomes (freq: 0.00006) and European Finnish in 1 of 25790 chromosomes (freq: 0.00004), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian or South Asian populations. The p.Ile608 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the Val variant impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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 uncertain significance. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 16, 2023 | Variant summary: MSH6 c.1822A>G (p.Ile608Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250564 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1822A>G has been reported in the literature with conflicting interpretations of pathogenicity ranging from VUS in settings of multigene panel testing for colorectal cancer (example, Yurgelun_2015) to a re-classification as Likely Benign based on patient-driven family studies using quantitative co-segregation likelihood ratios and a unified framework for Bayesian analysis with ACMG/AMP criteria (example, Tsai_2019). Additionally, the variant was identified in a healthy control case in a study assessing colorectal cancer or polyps cases (Rosenthal_2018) and was also identified in a case from The Cancer Genome Atlas database, however no additional information was provided (Yehia_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely Benign, n=1; VUS, n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
.;.;T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
.;T;T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;L;.;.
PrimateAI
Benign
T
PROVEAN
Benign
.;N;N;.;N
REVEL
Benign
Sift
Benign
.;T;T;.;T
Sift4G
Benign
T;T;T;T;T
Polyphen
0.0020
.;.;B;.;.
Vest4
MVP
ClinPred
T
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RBP_binding_hub_radar
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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