rs201080919
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_000179.3(MSH6):c.3801+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000508 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000051 ( 0 hom. )
Consequence
MSH6
NM_000179.3 splice_region, intron
NM_000179.3 splice_region, intron
Scores
2
Splicing: ADA: 0.9992
2
Clinical Significance
Conservation
PhyloP100: 5.02
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 2-47806363-G-A is Benign according to our data. Variant chr2-47806363-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 186876.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=3}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MSH6 | NM_000179.3 | c.3801+5G>A | splice_region_variant, intron_variant | ENST00000234420.11 | NP_000170.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MSH6 | ENST00000234420.11 | c.3801+5G>A | splice_region_variant, intron_variant | 1 | NM_000179.3 | ENSP00000234420.5 |
Frequencies
GnomAD3 genomes 0.0000526 AC: 8AN: 152164Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000876 AC: 22AN: 251178Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135770
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GnomAD4 exome AF: 0.0000506 AC: 74AN: 1461822Hom.: 0 Cov.: 33 AF XY: 0.0000550 AC XY: 40AN XY: 727204
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GnomAD4 genome 0.0000525 AC: 8AN: 152282Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74452
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:9
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Lynch syndrome 5 Uncertain:2Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 07, 2016 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 28, 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 | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not provided Uncertain:1Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 16, 2019 | In silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in individuals with colorectal and breast cancers (Shirts 2016, Tung 2016, Yurgelun 2017); This variant is associated with the following publications: (PMID: 28135145, 31642931, 25318351, 26976419, 26845104) - |
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 30, 2021 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH6 c.3801+5G>A variant was identified in 3 of 4640 proband chromosomes (frequency: 0.0006) from individuals or families with breast, ovarian or colon cancer (Shirts 2016, Yorczyk 2014, Tung 2016). The variant was also identified in the following databases: dbSNP (ID: rs201080919) as “With other allele” and ClinVar (2x as likely benign by Ambry Genetics and University of Washington, 5x as uncertain significance by Invitae, GeneDx, Counsyl, Integrated Genetics, Illumina Clinical services) The variant was not identified in COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 22 of 245988 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5476 chromosomes (freq: 0.0002), Latino in 7 of 33544 chromosomes (freq: 0.0002), European Non-Finnish in 9 of 111508 chromosomes (freq: 0.00008), Ashkenazi Jewish in 5 of 9848 chromosomes (freq: 0.0005), while the variant was not observed in the African, East Asian, European Finnish, or South Asian populations. The c.3801+5G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. 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 cancer-predisposing syndrome Uncertain:1Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 21, 2016 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 24, 2019 | This alteration is classified as likely 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. - |
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 22, 2021 | - - |
Lynch syndrome Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 23, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Dec 20, 2016 | Communication from other laboratories about other patients with this variant and no family history of colorectal cancer. Splicing anlaysis indicates 95% full length product. - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 11, 2024 | Variant summary: MSH6 c.3801+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predict the variant weakens the canonical 5' splicing donor site. Three predict the variant abolishes the canonical 5' splicing donor site. However, RNA studies demonstrate this variant has no abnormal splicing (Karam_2019). The variant allele was found at a frequency of 8.8e-05 in 251178 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome (8.8e-05 vs 0.00014), allowing no conclusion about variant significance. c.3801+5G>A has been reported in the literature in individuals affected with breast cancer, colorectal cancer, Lynch Syndrome as well as in healthy individuals and also as a VUS in settings of multigene panel testing (example, Shirts_2016, Tung_2016, Yorczyk_2015, Yurgelun_2017, Karam_2019, de Oliveira_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least two co-occurrences with other pathogenic variant(s) have been observed at our laboratory (RB1 c.1399C>T, p.Arg467X; BRCA1 c.2411_2412delAG, p.Gln804LeufsX5), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34445333, 31642931, 26845104, 26976419, 25318351, 28135145, 35534704). ClinVar contains an entry for this variant (Variation ID: 186876). Based on the evidence outlined above, the variant was classified as likely benign. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
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Benign
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Benign
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dbscSNV1_ADA
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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