Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM5
The NM_000179.3(MSH6):c.4000C>T(p.Arg1334Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 1,606,498 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1334Q) has been classified as Pathogenic.
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]
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM5
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PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr2-47806651-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 89506.Status of the report is reviewed_by_expert_panel, 3 stars.
Uncertain significance, criteria provided, single submitter
clinical testing
Counsyl
Dec 28, 2015
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Myriad Genetics, Inc.
Mar 28, 2023
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Aug 03, 2023
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal and family history of colon cancer as well as individuals with a personal history of breast cancer, one of whom also had pancreatic cancer (Chubb et al., 2015; Dudley et al., 2018; Hu et al., 2022; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 25559809, 25275298, 29360161, 31391288, 23415222, 33471991, 35449176, 21120944, 12019211, 17531815, 25370038) -
Uncertain significance, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Oct 12, 2023
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
clinical testing
Color Diagnostics, LLC DBA Color Health
Nov 01, 2022
This missense variant replaces arginine with tryptophan at codon 1334 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected by early-onset, familial colorectal cancer (PMID: 25559809). This variant has been identified in 11/275890 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.4001G>A (p.Arg1334Gln), is considered to be disease-causing (ClinVar variation ID: 89506), suggesting that this position is important for the protein function. 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
Aug 06, 2021
Variant summary: MSH6 c.4000C>T (p.Arg1334Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.7e-05 in 244568 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4000C>T has been reported in the literature as somatic occurrence in individuals affected with chronic lymphocytic leukemia, HNSCC, polyposis and endometrial cancer (Landau_2013, Martin_2014, Elsayed_2015) and as germline occurrence in individuals affected with cancer including colorectal, pancreatic and breast cancer (Chubb_2015, Dudley_2018, Li_2020, Dorling_2021), but it was also reported in controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Nov 30, 2023
This missense variant replaces arginine with tryptophan at codon 1334 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected by early-onset, familial colorectal cancer (PMID: 25559809). This variant has been identified in 11/275890 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.4001G>A (p.Arg1334Gln), is considered to be disease-causing (ClinVar variation ID: 89506), suggesting that this position is important for the protein function. 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
Invitae
Jan 24, 2024
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1334 of the MSH6 protein (p.Arg1334Trp). This variant is present in population databases (rs773763465, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer, breast cancer, and/or pancreatic cancer (PMID: 25559809, 29360161, 35449176). ClinVar contains an entry for this variant (Variation ID: 184389). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). 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