2-47806443-TTTC-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP6

The NM_000179.3(MSH6):c.3802-6_3802-4delCTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MSH6
NM_000179.3 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 1.54

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 2-47806443-TTTC-T is Benign according to our data. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679. Variant chr2-47806443-TTTC-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 141679.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.3802-6_3802-4delCTT		splice_region_variant, intron_variant	Intron 8 of 9	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.3802-6_3802-4delCTT		splice_region_variant, intron_variant	Intron 8 of 9	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250980

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

6.84e-7

AC:

AN:

1461762

Hom.:

AF XY:

0.00

AC XY:

AN XY:

727180

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111946

Other (OTH)

AF:

0.00

AC:

AN:

60390

⚠️ 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: 0.375

Heterozygous variant carriers

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

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 28, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MSH6 c.3802-6_3802-4delCTT alters a nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 3' acceptor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.2e-07 in 1614076 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3802-6_3802-4delCTT in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 141679). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Lynch syndrome

Uncertain:1

May 30, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant causes a deletion of nucleotides CTT in intron 8 of the MSH6 gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/250980 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 provided

Uncertain:1

Apr 23, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MSH6 c.3802-6_3802-4del variant has not been reported in individuals with MSH6-related conditions in the published literature. The frequency of this variant in the general population, 0.000004 (1/250980 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 MSH6 mRNA splicing yielded inconclusive findings. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Feb 05, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.5

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over