2-47799713-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BP6
The ENST00000234420.11(MSH6):c.1730G>A(p.Arg577His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000756 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R577C) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000074 ( 0 hom. )
Consequence
MSH6
ENST00000234420.11 missense
ENST00000234420.11 missense
Scores
10
7
2
Clinical Significance
Conservation
PhyloP100: 9.84
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 Uncertain_significance. Variant got 0 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.84
BP6
Variant 2-47799713-G-A is Benign according to our data. Variant chr2-47799713-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134852.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=14, not_provided=1}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MSH6 | NM_000179.3 | c.1730G>A | p.Arg577His | 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.1730G>A | p.Arg577His | missense_variant | 4/10 | 1 | NM_000179.3 | ENSP00000234420 | P4 |
Frequencies
GnomAD3 genomes 0.0000920 AC: 14AN: 152150Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000400 AC: 10AN: 250236Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135676
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GnomAD4 exome AF: 0.0000739 AC: 108AN: 1461886Hom.: 0 Cov.: 34 AF XY: 0.0000591 AC XY: 43AN XY: 727244
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GnomAD4 genome 0.0000919 AC: 14AN: 152268Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74446
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:15Benign:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:5
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 17, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 06, 2023 | In the published literature, this variant has been reported in affected individuals with breast cancer (PMIDs: 32885271 (2021), 33471991 (2021), 33606809 (2021), and 35264596 (2022)), endometrial cancer (PMID: 27443514 (2016)), pancreatic cancer (PMID: 27449771 (2016)), tubulovillous adenomas (PMID: 26436109 (2015)), and autism (PMIDs: 34011629 (2021), 31785789 (2019), and 25363768 (2014)). In addition, this variant has been reported in control individuals (PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.000087 (3/34586 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
| 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 | GeneDx | Sep 21, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with pancreatic, endometrial, breast, and other cancers (Lu et al., 2015; Ring et al., 2016; Yang et al., 2016; Lerner-Ellis et al., 2021; Sandoval et al., 2021; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 26510091, 34011629, 31253177, 24728327, 23621914, 26546047, 27449771, 27443514, 26689913, 25363768, 31104363, 26436109, 31785789, 21120944, 17531815, Giacomazzi2022[preprint], 35264596, 35982160, 35982159, 32885271, 33606809, 25085752, 23729658) - |
| Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Lynch syndrome 5 Uncertain:2Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 29, 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]. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 14, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Nov 13, 2023 | The MSH6 c.1730G>A (p.Arg577His) missense change has a maximum subpopulation frequency of 0.0087% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but this prediction has not been confirmed by functional studies. This variant has been reported in individuals affected with endometrial, pancreatic, ovarian, and breast cancer (PMID: 26689913, 27443514, 27449771, 32885271, 33606809), and it has also been observed in an unaffected individual (PMID: 24728327). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
Lynch syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 29, 2024 | This missense variant replaces arginine with histidine at codon 577 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with endometrial, pancreatic and breast cancer (PMID: 26689913, 27443514, 27449771, 32885271, 33606809, 35264596) and an unaffected individual (PMID: 24728327). This variant has been identified in 10/250236 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 27, 2024 | The p.R577H variant (also known as c.1730G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1730. The arginine at codon 577 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in cohorts of breast and endometrial cancer patients (Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Ring KL et al. Mod Pathol. 2016 Nov;29(11):1381-1389; Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363; erner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). However, this variant was also identified in a cohort of 681 ancestrally diverse, healthy subjects under the age of 50 (Bodian DL et al. PLoS ONE. 2014 Apr;9:e94554). This alteration (designated as rs376220212) also co-occurred with an MSH2 missense alteration in one of 25 asymptomatic adults undergoing whole exome sequencing; this individual was found to have two tubulovillous adenomas at age 50 (Pillar N et al. Mol. Genet. Genomic Med. 2015 Sep;3:433-9). The p.R577H variant was classified as deleterious by authors who identified it in a CDKN2A mutation positive patient with pancreatic cancer and in 0 of 1001 controls. This determination, however, was made based on the meta likelihood ratio prediction tool incorporating in silico algorithms and allele frequency only (Yang XR et al. Hum. Genet. 2016 Nov;135:1241-1249). 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 variant remains unclear. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 04, 2023 | This missense variant replaces arginine with histidine at codon 577 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with endometrial, pancreatic and breast cancer (PMID: 26689913, 27443514, 27449771, 32885271, 33606809) and an unaffected individual (PMID: 24728327). This variant has been identified in 10/250236 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. - |
Endometrial carcinoma Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Nov 25, 2022 | ACMG classification criteria: PM2 supporting - |
not specified Uncertain:1Other:1
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 24, 2019 | Variant summary: MSH6 c.1730G>A (p.Arg577His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250236 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (4e-05 vs 0.00014), allowing no conclusion about variant significance. c.1730G>A has been reported in the literature in individuals affected with tubulovillous adenomas, endometrial carcinoma or pancreatic cancer (Pillar_2015, Ring_2016, Yang_2016). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MSH6 c.2677_2678delCT, p.Leu893AlafsX6), providing supporting evidence for a benign role. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Lynch-like syndrome Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Constitutional Genetics Lab, Leon Berard Cancer Center | Jul 01, 2019 | - - |
Carcinoma of colon Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH6 p.Arg577His variant was identified in a study of 114 cancer susceptibility genes, in individuals with 12 different cancer types, in 1 of 8068 proband chromosomes (frequency: 0.0001) from individuals or families with lung adenocarcinoma (Lu 2015) and was present in 1 of 1362 control chromosomes (frequency: 0.0007) from healthy individuals (Bodian 2014). The variant was also identified in dbSBP (ID: rs376220212) as “With Uncertain significance allele,” ClinVar (as uncertain significance), Clinvitae (as uncertain significance), Cosmic, UMD-LSDB (co-occurring with a pathogenic MSH6 variant p.Leu893AlafsX6), as well as in our laboratory co-occurring with a pathogenic APC variant (p.Tyr1027IlefsX10), increasing the likelihood that the p.Arg577His variant does not have clinical significance. The variant was not identified in MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database. The variant was identified in control databases in 10 of 245960 chromosomes at a frequency of 0.000041 in the following populations: African in 1 of 15286 chromosomes (freq. 0.000065), Latino in 3 of 33578 chromosomes (freq. 0.000089), and European (Non-Finnish) in 6 of 111440 chromosomes (freq. 0.00005) populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Arg577His residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the DNA mismatch repair protein MutS, connector domain DNA mismatch repair protein MSH6 functional domain(s) increasing the likelihood that it may have clinical significance. 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. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
.;.;D;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;.;H;.;.
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
1.0
.;.;D;.;.
Vest4
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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