rs377746844
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_000179.3(MSH6):c.3438+11_3438+14del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,614,182 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000099 ( 2 hom. )
Consequence
MSH6
NM_000179.3 intron
NM_000179.3 intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.953
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 Benign. Variant got -16 ACMG points.
BP6
?
Variant 2-47803695-TCTTA-T is Benign according to our data. Variant chr2-47803695-TCTTA-T is described in ClinVar as [Likely_benign]. Clinvar id is 89384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47803695-TCTTA-T is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00023 (35/152316) while in subpopulation EAS AF= 0.00193 (10/5184). AF 95% confidence interval is 0.00105. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 2 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.3438+11_3438+14del | intron_variant | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.3438+11_3438+14del | intron_variant | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000230 AC: 35AN: 152198Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000219 AC: 55AN: 250742Hom.: 1 AF XY: 0.000206 AC XY: 28AN XY: 135732
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GnomAD4 exome AF: 0.0000985 AC: 144AN: 1461866Hom.: 2 AF XY: 0.0000935 AC XY: 68AN XY: 727236
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GnomAD4 genome ? AF: 0.000230 AC: 35AN: 152316Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17AN XY: 74482
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:7
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 15, 2018 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 04, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 11, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 12, 2017 | Variant summary: The MSH6 c.3438+11_3438+14delCTTA variant involves the alteration of 4 intronic nucleotides. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 27/120966 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.002081 (18/8650). This frequency is about 15 times the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. Multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Additionally, the variant was detected in an internal specimen which also carries likely pathogenic MLH1 c.347delC. Taken together, this variant is classified as benign. - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Hereditary cancer-predisposing syndrome Benign:4
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 10, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 28, 2014 | The variant is found in BR-OV-HEREDIC panel(s). - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 09, 2019 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 26, 2015 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 02, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Carcinoma of colon Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH6 c.3438+11_3438+14del variant was identified in 1 of 68 proband chromosomes (frequency: 0.015) from individuals or families with Lynch syndrome (Chan 1999). The variant was also identified in the following databases: dbSNP (ID: rs377746844) as “With Uncertain significance allele”, ClinVar (as uncertain significance, reviewed by expert panel), Clinvitae (as benign, likely benign, and uncertain significance), COGR, Insight Colon Cancer Gene Variant Database (as Class 3: uncertain), and Insight Hereditary Tumors Database (as Class 3: uncertain). The variant was not identified in Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant Database. The variant was identified by our laboratory in 2 individuals with Lynch syndrome. The variant was identified in control databases in 63 of 277008 chromosomes (1 homozygous) at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: East Asian in 39 of 18864 chromosomes (freq: 0.002), “Other” in 5 of 6460 chromosomes (freq: 0.0008), African in 9 of 24016 chromosomes (freq: 0.0004), European Non-Finnish in 9 of 126542 chromosomes (freq: 0.00007), South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish, European (Finnish), and Latino populations. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the loss of a cryptic splice acceptor site. 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. - |
Lynch syndrome 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Sep 28, 2016 | - - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 05, 2023 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at