2-47806751-CTTTTTTTTTTTTTTT-CTTTTTTTTTTT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000179.3(MSH6):c.4002-13_4002-10delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,444,038 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000029 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

MSH6
NM_000179.3 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.166

Publications

0 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: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 2-47806751-CTTTT-C is Benign according to our data. Variant chr2-47806751-CTTTT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1802702.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.4002-13_4002-10delTTTT		intron_variant	Intron 9 of 9	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9
FBXO11	NM_001190274.2 link	c.1363_1366delAAAA		downstream_gene_variant		ENST00000403359.8	NP_001177203.1	Q86XK2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 link	c.4002-13_4002-10delTTTT		intron_variant	Intron 9 of 9	1	NM_000179.3	ENSP00000234420.5		P52701-1
FBXO11	ENST00000403359.8 link	c.1363_1366delAAAA		downstream_gene_variant		1	NM_001190274.2	ENSP00000384823.4		Q86XK2-1

Frequencies

GnomAD3 genomes

AF:

0.0000289

AC:

AN:

138394

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000527

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000235

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000157

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000275

AC:

359

AN:

1305644

Hom.:

AF XY:

0.000268

AC XY:

175

AN XY:

651888

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00214

AC:

AN:

28056

American (AMR)

AF:

0.000467

AC:

AN:

36408

Ashkenazi Jewish (ASJ)

AF:

0.000206

AC:

AN:

24232

East Asian (EAS)

AF:

0.0000289

AC:

AN:

34562

South Asian (SAS)

AF:

0.000290

AC:

AN:

75944

European-Finnish (FIN)

AF:

0.000327

AC:

AN:

42854

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5176

European-Non Finnish (NFE)

AF:

0.000227

AC:

228

AN:

1004182

Other (OTH)

AF:

0.000221

AC:

AN:

54230

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.303

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000289

AC:

AN:

138394

Hom.:

Cov.:

AF XY:

0.0000449

AC XY:

AN XY:

66768

show subpopulations

African (AFR)

AF:

0.0000527

AC:

AN:

37976

American (AMR)

AF:

0.00

AC:

AN:

13576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3320

East Asian (EAS)

AF:

0.00

AC:

AN:

4420

South Asian (SAS)

AF:

0.000235

AC:

AN:

4248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7960

Middle Eastern (MID)

AF:

0.00

AC:

AN:

296

European-Non Finnish (NFE)

AF:

0.0000157

AC:

AN:

63842

Other (OTH)

AF:

0.00

AC:

AN:

1886

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

174

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 03, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MSH6 c.4002-13_4002-10del variant has not been reported in individuals with MSH6-related conditions in the published literature. The frequency of this variant in the general population, 0.000029 (4/138394 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect MSH6 mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breast and/or ovarian cancer

Benign:1

Jun 09, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.17

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over