rs751683437
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting
The NM_000179.3(MSH6):βc.2561_2563delβ(p.Lys854del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,613,252 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: π 0.000013 ( 0 hom., cov: 32)
Exomes π: 0.000025 ( 0 hom. )
Consequence
MSH6
NM_000179.3 inframe_deletion
NM_000179.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.26
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 1 ACMG points.
PM4
?
Nonframeshift variant in NON repetitive region in NM_000179.3. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.2561_2563del | p.Lys854del | inframe_deletion | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.2561_2563del | p.Lys854del | inframe_deletion | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152000Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000201 AC: 5AN: 249108Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135170
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GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461252Hom.: 0 AF XY: 0.0000248 AC XY: 18AN XY: 726958
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 10, 2022 | This variant causes a deletion of 1 amino acid from the MSH6 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in trans with a pathogenic frameshift mutation in an individual affected with early-onset Lynch syndrome (PMID: 24068316, 26318770). This variant has also been observed as a somatic variant in a tumor sample from in an individual affected with Lynch syndrome, who carried a pathogenic MSH2 mutation (inversion of exons 1 - 7 inversion, also known as Boland mutation) in the germline (PMID: 29755653). This variant has been identified in 5/249108 chromosomes 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 19, 2023 | The c.2561_2563delAGA variant (also known as p.K854del) is located in coding exon 4 of the MSH6 gene. This variant results from an in-frame AGA deletion at nucleotide positions 2561 to 2563, causing the removal of a lysine residue at codon 854. This alteration has been reported in a French patient with a clinical diagnosis of Constitutional Mismatch Repair Deficiency (CMMRD) syndrome in conjunction with a known MSH6 pathogenic mutation; however, authors note that the clinical presentation is more consistent with an early form of Lynch syndrome than with CMMRD, suggesting that this alteration may not be completely inactivating (Bougeard G et al. Fam. Cancer. 2014 Mar;13:131-5; Lavoine N et al. J. Med. Genet. 2015 Nov;52:770-8). This alteration was also detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This alteration has also been identified in several individuals with Lynch-associated tumors that were microsatellite stable (MSS) and/or had normal mismatch repair protein expression on immunohistochemistry (IHC) (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 15, 2021 | - - |
not specified Uncertain:2
Uncertain significance, no assertion criteria provided | research | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 11, 2023 | Variant summary: MSH6 c.2561_2563delAGA (p.Lys854del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 249108 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2561_2563delAGA has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer or breast cancer (Bougeard_2014, Gray_2018, Hampel_2018, Nikitin_2020, Salvador_2018, Tung_2014, Lin_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variant has been reported in a patient with Constitutional Mismatch Repair-Deficiency Syndrome (MSH6 c.3261dupC, p.Phe1088Leufs*5), providing supporting evidence for a benign role (Bodo_2015). 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: 26116798, 24068316, 29755653, 29596542, 35752529, 32547938, 30702970, 25186627). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 15, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 23, 2023 | In-frame deletion of 1 amino acid in a non-repeat region; Observed with a pathogenic MSH6 variant on the opposite allele (in trans) in a case of possible constitutional mismatch repair deficiency (CMMR-D), but analysis of all mismatch repair genes was not performed and therefore this variant may not be responsible for the phenotype (Bougeard et al., 2014); Observed in individuals with breast cancer (Tung et al., 2015; Nikitin et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Located in the critical Lever domain (Warren et al., 2007; Kansikas et al., 2011); This variant is associated with the following publications: (PMID: 29596542, 30877237, 26318770, 26116798, 29755653, 17531815, 21120944, 30702970, 32547938, 35752529, 25186627, 24068316) - |
Lynch-like syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Constitutional Genetics Lab, Leon Berard Cancer Center | Jul 01, 2019 | - - |
Lynch syndrome 5 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 09, 2023 | - - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This variant, c.2561_2563del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Lys854del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs751683437, gnomAD 0.004%). This variant has been observed in individual(s) with constitutional mismatch repair deficiency syndrome and breast cancer and clinical features of Lynch syndrome (PMID: 25186627, 26318770, 32547938; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 142970). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Endometrial carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 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