2-47806751-CTTTTTTTTTTTTTTT-CTTTTTTTTTTTTT

Variant names:

• chr2-47806751-CTT-C
• rs59056100
• NM_000179.3:c.4002-11_4002-10delTT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000179.3(MSH6):​c.4002-11_4002-10delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0507 in 1,399,250 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 0)
  • Exomes 𝑓: 0.056 (1 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.871
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 2-47806751-CTT-C is Benign according to our data. Variant chr2-47806751-CTT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 89509.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00386 (534/138370) while in subpopulation SAS AF = 0.00686 (29/4230). AF 95% confidence interval is 0.0049. There are 2 homozygotes in GnomAd4. There are 262 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.4002-11_4002-10delTT		intron_variant	Intron 9 of 9	ENST00000234420.11	NP_000170.1
FBXO11	NM_001190274.2	c.*1365_*1366delAA		downstream_gene_variant		ENST00000403359.8	NP_001177203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.4002-11_4002-10delTT		intron_variant	Intron 9 of 9	1	NM_000179.3	ENSP00000234420.5
FBXO11	ENST00000403359.8	c.*1365_*1366delAA		downstream_gene_variant		1	NM_001190274.2	ENSP00000384823.4

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 531 AN: 138316 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00273

Gnomad ASJ AF: 0.00241

Gnomad EAS AF: 0.00294

Gnomad SAS AF: 0.00682

Gnomad FIN AF: 0.00416

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00481

Gnomad OTH AF: 0.00266

GnomAD4 exome AF: 0.0558 AC: 70353 AN: 1260880 Hom.: 1 AF XY: 0.0562 AC XY: 35400 AN XY: 629462

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

African (AFR) AF: 0.0568 AC: 1549 AN: 27286

American (AMR) AF: 0.0478 AC: 1682 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.0707 AC: 1651 AN: 23362

East Asian (EAS) AF: 0.0549 AC: 1827 AN: 33288

South Asian (SAS) AF: 0.0492 AC: 3624 AN: 73594

European-Finnish (FIN) AF: 0.0678 AC: 2810 AN: 41434

Middle Eastern (MID) AF: 0.0488 AC: 246 AN: 5040

European-Non Finnish (NFE) AF: 0.0558 AC: 54082 AN: 969260

Other (OTH) AF: 0.0550 AC: 2882 AN: 52418

⚠️ 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.

GnomAD4 genome AF: 0.00386 AC: 534 AN: 138370 Hom.: 2 Cov.: 0 AF XY: 0.00392 AC XY: 262 AN XY: 66798

African (AFR) AF: 0.00265 AC: 101 AN: 38048

American (AMR) AF: 0.00272 AC: 37 AN: 13588

Ashkenazi Jewish (ASJ) AF: 0.00241 AC: 8 AN: 3316

East Asian (EAS) AF: 0.00295 AC: 13 AN: 4408

South Asian (SAS) AF: 0.00686 AC: 29 AN: 4230

European-Finnish (FIN) AF: 0.00416 AC: 33 AN: 7938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.00483 AC: 308 AN: 63810

Other (OTH) AF: 0.00264 AC: 5 AN: 1892

Alfa AF: 0.0297 Hom.: 174

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Dec 02, 2015

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted MSH6 c.4002-13_4002-12delTTinsAA or IVS9-13_IVS9-12delTTinsAA and consists of a deletion and insertion of two nucleotides at the -13 and -12 positions of intron 9 of the MSH6 gene.The normal sequence, with the bases that are deleted in braces and inserted in brackets, is tttt{tt}[aa]ttaa.Multiple in silico models predict this variant to destroy the nearby natural acceptor site, and to possibly cause abnormal gene splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown.MSH6 c.4002-13_4002-12delTTinsAA was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations.This variant has not, to our knowledge, been published in the literature as pathogenic or benign.The nucleotides that are altered are not conserved.Based on currently available information, it is unclear whether MSH6 c.4002-13_4002-12delTTinsAA is pathogenic or benign.We consider it to be a variant of uncertain significance. -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 06, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 5 Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

Apr 22, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.87
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs59056100; hg19: chr2-48033890; COSMIC: COSV109409077;