rs41294988
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000179.3(MSH6):āc.38A>Cā(p.Lys13Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,459,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.000016 ( 0 hom. )
Consequence
MSH6
NM_000179.3 missense
NM_000179.3 missense
Scores
2
11
6
Clinical Significance
Conservation
PhyloP100: 2.35
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.38A>C | p.Lys13Thr | missense_variant | 1/10 | ENST00000234420.11 | NP_000170.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.38A>C | p.Lys13Thr | missense_variant | 1/10 | 1 | NM_000179.3 | ENSP00000234420.5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1459880Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16AN XY: 726328
GnomAD4 exome
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24
AN:
1459880
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30
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16
AN XY:
726328
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Lynch syndrome 5 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 30, 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 05, 2017 | - - |
Lynch syndrome Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 02, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant replaces lysine with threonine at codon 13 of the MSH6 protein. Computational prediction tool 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). 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 colorectal cancer (PMID: 18033691). This variant has not been identified 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 provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 05, 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; Published functional studies demonstrate intermediate MMR activity as compared to wild-type (Drost et al., 2020); This variant is associated with the following publications: (PMID: 19389263, 23621914, 21153778, 26333163, Yambert2022[article], 18033691, 31965077) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 01, 2023 | In the published literature, this variant has been reported in an individual with colorectal cancer (PMID: 18033691 (2008)). Published functional studies to determine the effect of this variant on protein function were inconclusive (PMID: 31965077 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2022 | The p.K13T variant (also known as c.38A>C), located in coding exon 1 of the MSH6 gene, results from an A to C substitution at nucleotide position 38. The lysine at codon 13 is replaced by threonine, an amino acid with similar properties. This alteration was identified in one of 932 colorectal cancer patients diagnosed under 55 years of age and was not seen in any of the 1104 control individuals; however, this individual’s tumor showed microsatellite stability and presence of MSH6 staining on immunohistochemistry and was therefore classified as "undefined" (Barnetson RA et al. Hum. Mutat. 2008 Mar;29:367-74). This amino acid position is highly 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 | Jun 21, 2023 | This missense variant replaces lysine with threonine at codon 13 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). A functional study has shown that this variant retained approximately 50% of wild-type mismatch repair activity (PMID: 31965077). This variant has been reported in an individual with mismatch repair stable colorectal cancer (PMID: 18033691). This variant has not been identified 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 | Genetic Services Laboratory, University of Chicago | Aug 07, 2018 | - - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 31, 2022 | This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 13 of the MSH6 protein (p.Lys13Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 18033691). ClinVar contains an entry for this variant (Variation ID: 36596). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MSH6 function (PMID: 31965077). 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 | Oct 19, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;D;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;.
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;.
REVEL
Uncertain
Sift
Uncertain
D;D;.
Sift4G
Uncertain
D;D;D
Polyphen
0.95
.;P;.
Vest4
MutPred
Loss of methylation at K13 (P = 0.0026);Loss of methylation at K13 (P = 0.0026);Loss of methylation at K13 (P = 0.0026);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at