rs863225412
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM4PP3PP5_Very_Strong
The NM_000179.3(MSH6):βc.3744_3773delβ(p.His1248_Ser1257del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,168 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 33)
Consequence
MSH6
NM_000179.3 inframe_deletion
NM_000179.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.85
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 Pathogenic. Variant got 15 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 16 uncertain in NM_000179.3
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000179.3.
PP3
?
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
Variant 2-47806296-ACTCACTACCATTCATTAGTAGAAGATTATT-A is Pathogenic according to our data. Variant chr2-47806296-ACTCACTACCATTCATTAGTAGAAGATTATT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.3744_3773del | p.His1248_Ser1257del | inframe_deletion | 8/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.3744_3773del | p.His1248_Ser1257del | inframe_deletion | 8/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251206Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135758
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74344
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 21, 2022 | The c.3744_3773del30 pathogenic mutation (also known as p.H1248_S1257del) is located in coding exon 8 of the MSH6 gene. This mutation results from an in-frame deletion of 30 nucleotides at positions 3744 to 3773 and causes the removal of 10 well-conserved amino acid residues at codons 1248 to 1257. This mutation has been seen in individuals with Lynch syndrome, including three families meeting Amsterdam criteria with tumor results from one family showing loss of MSH6 protein on immunohistochemistry (Chang K et al. JAMA Oncol, 2018 08;4:1085-1092; Ambry internal data). This mutation was also reported in a woman whose endometrial tumor demonstrated loss of MSH6 on IHC (Dedeurwaerdere F et al. Sci Rep, 2021 06;11:12880). In addition, this mutation segregated with disease in the three families with a combined LOD score of 1.8 (Ambry internal data). Based on internal structural analysis, this alteration results in a distortion of the α-helix of a protein-protein interface of MSH6, significantly altering the surrounding residues (Warren JJ et al. Mol. Cell. 2007 May; 26(4):579-92). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 08, 2023 | This variant causes an in-frame deletion of 10 amino acids at exon 8 of the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome and Lynch syndrome-associated cancer (PMID: 29710228; ClinVar SCV000580154.5, SCV000624910.8), and in an individual affected with mismatch repair deficient endometrial cancer (PMID: 34145315).This variant has been identified in 1/251206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Hereditary nonpolyposis colon cancer Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 08, 2021 | Variant summary: MSH6 c.3744_3773del30 (p.His1248_Ser1257del) results in an in-frame deletion that is predicted to remove 10 amino acids from the encoded protein. The variant allele was found at a frequency of 4e-06 in 251206 control chromosomes. c.3744_3773del30 has been reported in the literature in individuals affected with Lynch Syndrome (Chang_2018). These data do not allow any conclusion about variant significance. Co-occurrences with a pathogenic variant has been reported (APC c.487C>T, p.Gln163X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and indicated that this variant co-segregates with lynch syndrome-related cancers in multiple families. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Lynch syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 15, 2023 | This variant causes an in-frame deletion of 10 amino acids at exon 8 of the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome and Lynch syndrome-associated cancer (PMID: 29710228; ClinVar SCV000580154.5, SCV000624910.8), and in an individual affected with mismatch repair deficient endometrial cancer (PMID: 34145315).This variant has been identified in 1/251206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 01, 2022 | In-frame deletion of 10 amino acids in a non-repeat region predicted to critically alter the protein: disrupts the ATPase domain (Warren et al., 2007, Kansikas et al., 2011); In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28765196, 25504618, 29922827, 17531815, 21120944, 34145315) - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | This variant, c.3744_3773del, results in the deletion of 10 amino acid(s) of the MSH6 protein (p.His1248_Ser1257del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has been observed in individuals with Lynch syndrome-related cancers and Lynch syndrome (Invitae; External communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218070). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. - |
Endometrial carcinoma Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 20, 2024 | - - |
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | research | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at