rs1361745058
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000179.3(MSH6):c.2001T>A(p.Asp667Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,144 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 Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D667H) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Consequence
MSH6
NM_000179.3 missense
NM_000179.3 missense
Scores
7
11
1
Clinical Significance
Conservation
PhyloP100: 1.21
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 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.822
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| MSH6 | NM_000179.3 | c.2001T>A | p.Asp667Glu | missense_variant | 4/10 | ENST00000234420.11 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MSH6 | ENST00000234420.11 | c.2001T>A | p.Asp667Glu | missense_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32
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GnomAD4 exome Cov.: 34
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GnomAD4 genome 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74320
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 27, 2022 | The p.D667E variant (also known as c.2001T>A), located in coding exon 4 of the MSH6 gene, results from a T to A substitution at nucleotide position 2001. The aspartic acid at codon 667 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is conserved. 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 05, 2023 | This missense variant replaces aspartic acid with glutamic acid at codon 667 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has not been identified 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. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 14, 2019 | Variant summary: MSH6 c.2001T>A (p.Asp667Glu) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245778 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2001T>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Lynch syndrome 5 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Oct 27, 2022 | The MSH6 c.2001T>A (p.Asp667Glu) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or constitutional mismatch repair deficiency. 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. - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 09, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 667 of the MSH6 protein (p.Asp667Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 455171). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;.;D;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D
M_CAP
Pathogenic
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
0.99
.;.;D;.;.
Vest4
MutPred
0.36
.;.;Loss of helix (P = 0.0558);.;.;
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