rs63751009
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_000179.3(MSH6):āc.1565A>Gā(p.Gln522Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,864 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: not found (cov: 32)
Exomes š: 0.0000075 ( 0 hom. )
Consequence
MSH6
NM_000179.3 missense
NM_000179.3 missense
Scores
4
6
9
Clinical Significance
Conservation
PhyloP100: 9.24
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 2-47799548-A-G is Benign according to our data. Variant chr2-47799548-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89200.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=7, not_provided=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.1565A>G | p.Gln522Arg | 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.1565A>G | p.Gln522Arg | missense_variant | 4/10 | 1 | NM_000179.3 | ENSP00000234420.5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251306Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135814
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GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461864Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8AN XY: 727232
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 29, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 15, 2023 | The p.Q522R variant (also known as c.1565A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1565. The glutamine at codon 522 is replaced by arginine, an amino acid with highly similar properties. This variant has been reported in multiple early-onset colorectal patients, including two whose tumors demonstrated intact MSH6 expression by IHC analysis (Berends MJ et al. Am. J. Hum. Genet. 2002 Jan; 70(1):26-37; Domingo E et al. Oncogene 2005 Jun; 24(24):3995-8; Niessen RC et al. Gut 2006 Dec; 55(12):1781-8). In an in vitro MMR assay, p.Q522R was classified as repair proficient due to its repair efficiency being significantly higher than repair-deficient controls (Drost M et al. Hum. Mutat. 2012 Mar; 33(3):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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 28, 2016 | - - |
Lynch syndrome 5 Uncertain:2Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 30, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 16, 2017 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Likely benign and reported on 09-17-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 10, 2019 | Variant summary: MSH6 c.1565A>G (p.Gln522Arg) results in a conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain (IPR007695). Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251306 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1565A>G has been reported in the literature in at least 3 individuals affected with colorectal cancer, however the associated tumors in 2 of these cases were noted to be microsatellite stable (Berends_2002, Domingo_2005). These reports therefore do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Experimental evidence evaluating an impact on protein function demonstrated the variant protein has a repair efficiency that was significantly higher than repair-deficient controls (~75% of the wild-type), therefore was concluded to be repair proficient in this assay (Drost_2012). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (4x) or likely benign (1x). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 04, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least four cases of early-onset colorectal cancers, most exhibiting normal MSI and/or IHC analyses, with no corresponding family having met Amsterdam I or II criteria for Lynch Syndrome (Berends et al., 2002; Domingo et al., 2005; Niessen et al., 2006); This variant is associated with the following publications: (PMID: 26333163, 11709755, 15782118, 24100870, 16636019, 18790734, 17531815, 21120944, 22102614) - |
Endometrial carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 24, 2024 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 19, 2023 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | curation | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Nov 19, 2024 | According to the ClinGen InSiGHT ACMG MSH6 v1.0.0 criteria we chose these criteria: PM2 (supporting pathogenic): Grpmax Filtering AF = 0.000006814 (thus < 0,00002), BP4 (supporting benign): Applied prior : 0.10, BP5 (supporting benign): Domingo 2005, Berends 2002, Niessen 2006: j3 1x CRC MSI-L, BS3 (supporting benign): Drost (2012), PMID: 22102614 --> repair proficient - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;.;T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
.;.;N;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;N;.;N
REVEL
Pathogenic
Sift
Benign
.;T;T;.;T
Sift4G
Benign
T;T;T;T;T
Polyphen
0.083
.;.;B;.;.
Vest4
MutPred
0.72
.;.;Gain of MoRF binding (P = 0.0298);.;.;
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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