2-47800236-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000179.3(MSH6):c.2253T>C(p.Asn751Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,614,188 control chromosomes in the GnomAD database, including 203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.019 ( 97 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 106 hom. )

Consequence

MSH6
NM_000179.3 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:22

Conservation

PhyloP100: -0.534

Publications

13 publications found

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]

MSH6 links:

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]

FBXO11 Gene-Disease associations (from GenCC):

intellectual developmental disorder with dysmorphic facies and behavioral abnormalities
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

FBXO11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 2-47800236-T-C is Benign according to our data. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800236-T-C is described in CliVar as Benign. Clinvar id is 36585.Status of the report is reviewed_by_expert_panel, 3 stars.

BP7

Synonymous conserved (PhyloP=-0.534 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.2253T>C	p.Asn751Asn	synonymous_variant	Exon 4 of 10	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 link	c.2253T>C	p.Asn751Asn	synonymous_variant	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.0185

AC:

2823

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0648

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00622

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00532

AC:

1335

AN:

251014

AF XY:

0.00361

show subpopulations

Gnomad AFR exome

AF:

0.0723

Gnomad AMR exome

AF:

0.00356

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000168

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00191

AC:

2787

AN:

1461870

Hom.:

106

Cov.:

AF XY:

0.00158

AC XY:

1151

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0653

AC:

2187

AN:

33478

American (AMR)

AF:

0.00436

AC:

195

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000112

AC:

125

AN:

1112000

Other (OTH)

AF:

0.00424

AC:

256

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

188

376

564

752

940

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0186

AC:

2832

AN:

152318

Hom.:

Cov.:

AF XY:

0.0178

AC XY:

1327

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0648

AC:

2694

AN:

41568

American (AMR)

AF:

0.00621

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68030

Other (OTH)

AF:

0.0109

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

129

257

386

514

643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00801

Hom.:

Bravo

AF:

0.0215

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:22

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Jun 07, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:5

Jul 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MSH6: BP4, BP7, BS1, BS2 -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Lynch syndrome 5

Benign:4

Apr 06, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 30, 2024

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Lynch syndrome

Benign:2

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing;curation

- -

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:research

MAF >1% -

Hereditary cancer-predisposing syndrome

Benign:2

Apr 07, 2015

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 18, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Carcinoma of colon

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The p.Asn751Asn variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located near a splice site. In addition, this variant has been identified in dbSNP (rs2020913) as a polymorphism at about 1% frequency in a Yoruban cohort and in the exome variant server at an elevated frequency (~6 %) in African American individuals. In summary, based on this information this variant is considered benign. (it should be noted that the individual identified by our laboratory was indicated as "Black") -

Breast and/or ovarian cancer

Benign:1

Nov 18, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

1.5

(source)

DANN

Benign

0.47

PhyloP100

-0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over