rs182024561
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_000179.3(MSH6):c.3601C>A(p.Leu1201Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1201R) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
MSH6
NM_000179.3 missense
NM_000179.3 missense
Scores
7
8
4
Clinical Significance
Conservation
PhyloP100: 4.56
Publications
0 publications found
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]
FBXO11 Gene-Disease associations (from GenCC):
- intellectual developmental disorder with dysmorphic facies and behavioral abnormalitiesInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 8 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 56 uncertain in NM_000179.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-47805663-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1733115.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.936
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Apr 27, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.3601C>A (p.L1201I) alteration is located in exon 7 (coding exon 7) of the MSH6 gene. This alteration results from a C to A substitution at nucleotide position 3601, causing the leucine (L) at amino acid position 1201 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;.;T;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;.;.;M;.
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;.;N;N
REVEL
Pathogenic
Sift
Pathogenic
.;D;.;D;D
Sift4G
Pathogenic
D;D;T;D;D
Polyphen
1.0
.;.;.;D;.
Vest4
MutPred
0.79
.;.;.;Gain of catalytic residue at L1201 (P = 0.0741);.;
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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