chr2-47799044-G-T
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000179.3(MSH6):c.1061G>T(p.Gly354Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )
Consequence
MSH6
NM_000179.3 missense
NM_000179.3 missense
Scores
2
7
10
Clinical Significance
Conservation
PhyloP100: 9.19
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 -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.23956472).
BP6
Variant 2-47799044-G-T is Benign according to our data. Variant chr2-47799044-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182618.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=10, Benign=1, Likely_benign=1}.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251202Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135762
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GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461882Hom.: 0 Cov.: 34 AF XY: 0.0000330 AC XY: 24AN XY: 727240
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74346
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:11Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 21, 2018 | The MSH6 c.1061G>T; p.Gly354Val variant (rs730881788), is reported in the literature in at least one individual with early-onset breast cancer (Maxwell 2015). This variant is reported as uncertain in ClinVar (Variation ID: 182618), and found in the general population with a low overall allele frequency of 0.003% (1/30980 alleles) in the Genome Aggregation Database. The glycine at codon 354 is not highly conserved, and computational programs that predict the effect of missense variants on the protein (SIFT, PolyPhen-2) suggest that this variant is tolerated. However, splicing algorithms (Alamut v.2.11) suggest this variant may have an impact on splicing by creating a cryptic donor site. Due to limited information, the clinical significance of the p.Gly354Val variant is uncertain at this time. REFERENCES Maxwell KN et al. Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet Med. 2015 Aug;17(8):630-8. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 14, 2023 | The frequency of this variant in the general population, 0.000004 (1/251202 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with early-onset breast cancer (PMID: 25503501(2015)), pancreatic cancer (PMID: 29945567(2018)) and pediatric acute lymphoblastic leukemia (PMID: 26580448 (2015)). In a large-scale breast cancer association study, the variant was observed in breast cancer cases and in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 20, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or other cancers (Maxwell et al., 2015; Zhang et al., 2015; Young et al., 2018); This variant is associated with the following publications: (PMID: 25503501, 26580448, 29945567) - |
Lynch syndrome 5 Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 29, 2023 | This variant is considered likely benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Apr 27, 2023 | The MSH6 c.1061G>T (p.Gly354Val) missense change has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and functional studies have not been performed. This variant has been reported in an individual with pancreatic cancer (PMID: 29945567). This variant has not been reported in individuals with Lynch syndrome or constitutional mismatch repair deficiency. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 26, 2017 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 05, 2023 | The p.G354V variant (also known as c.1061G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 1061. The glycine at codon 354 is replaced by valine, an amino acid with dissimilar properties. This alteration has been reported in one individual with early-onset breast cancer and in a pediatric patient diagnosed with acute lymphocytic leukemia (Maxwell KN et al. Genet. Med. 2015 Aug;17(8):630-8; Zhang J et al. N. Engl. J. Med. 2015 Dec;373(24):2336-2346). This alteration has also been reported in one individual with pancreatic cancer (Young E et al. BMC Cancer 2018 Jun;18(1):697). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 09, 2023 | This missense variant replaces glycine with valine at codon 354 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25503501) and an individual affected with childhood acute lymphoblastic leukemia (PMID: 26580448). This variant has been identified in 1/251202 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 08, 2024 | Variant summary: MSH6 c.1061G>T (p.Gly354Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.1e-05 in 1614086 control chromosomes (gnomAD v.4.0.0). This frequency is not significantly higher than estimated for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer (3.1e-05 vs 0.00014), allowing no conclusion about variant significance. c.1061G>T has been reported in the literature in at least one individual affected with early onset breast cancer (Maxwell_2015) and in individuals with other cancers without strong evidence for causality (e.g. Zhang_2015, Young_2018). These reports do not provide unequivocal conclusions about association of the variant with disease. 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: 25503501, 26580448, 29945567). ClinVar contains an entry for this variant (Variation ID: 182618). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 13, 2021 | - - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 11, 2024 | This missense variant replaces glycine with valine at codon 354 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25503501) and an individual affected with childhood acute lymphoblastic leukemia (PMID: 26580448). This variant has been identified in 1/251202 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. - |
MSH6-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 11, 2024 | The MSH6 c.1061G>T variant is predicted to result in the amino acid substitution p.Gly354Val. This variant has been reported in at least one individual with early-onset breast cancer (Maxwell et al. 2015. PubMed ID: 25503501) and an individual with acute lymphocytic leukemia (Zhang et al. 2015. PubMed ID: 26580448, Table S4a). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain significance by majority of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182618/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2025 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;.;T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;.;M;.;.
PrimateAI
Benign
T
PROVEAN
Benign
.;N;N;.;N
REVEL
Uncertain
Sift
Uncertain
.;D;D;.;D
Sift4G
Benign
T;D;D;D;T
Polyphen
0.0060
.;.;B;.;.
Vest4
MutPred
0.11
.;.;Loss of glycosylation at S353 (P = 0.0558);.;.;
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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Splicing
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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