2-47804995-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000179.3(MSH6):​c.3524C>T​(p.Thr1175Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

15
2
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 7.57
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSH6NM_000179.3 linkc.3524C>T p.Thr1175Ile missense_variant 6/10 ENST00000234420.11 NP_000170.1 P52701-1Q3SWU9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSH6ENST00000234420.11 linkc.3524C>T p.Thr1175Ile missense_variant 6/101 NM_000179.3 ENSP00000234420.5 P52701-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152146
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251268
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135812
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461680
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727158
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152264
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthAug 15, 2019This missense variant replaces threonine with isoleucine at codon 1175 of the MSH6 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/282662 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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 submitterclinical testingAmbry GeneticsFeb 07, 2024The p.T1175I variant (also known as c.3524C>T), located in coding exon 6 of the MSH6 gene, results from a C to T substitution at nucleotide position 3524. The threonine at codon 1175 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Feb 08, 2022- -
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJun 11, 2024This missense variant replaces threonine with isoleucine at codon 1175 of the MSH6 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/282662 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxSep 20, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17531815, 21120944) -
Endometrial carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsJan 23, 2024- -
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 23, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.39
.;.;T;D;.
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.99
.;D;D;D;D
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D
MetaSVM
Pathogenic
0.84
D
MutationAssessor
Pathogenic
3.0
.;.;.;M;.
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-5.6
.;D;.;D;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
.;D;.;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D
Polyphen
1.0
.;.;.;D;.
Vest4
0.99
MutPred
0.88
.;.;.;Loss of phosphorylation at T1175 (P = 0.0553);.;
MVP
0.97
ClinPred
0.99
D
GERP RS
5.2
Varity_R
0.93
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs369583604; hg19: chr2-48032134; API