2-47806751-CTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTT

Variant names:

• chr2-47806751-CT-C
• rs59056100
• NM_000179.3:c.4002-10delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000179.3(MSH6):​c.4002-10delT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.28 (4792 hom., cov: 0)
  • Exomes 𝑓: 0.38 (866 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Likely benign reviewed by expert panel B:13
• Conservation: PhyloP100: -1.08
• 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 -16 ACMG points.

• BP6: Variant 2-47806751-CT-C is Benign according to our data. Variant chr2-47806751-CT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 89508.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.4002-10delT		intron_variant	Intron 9 of 9	ENST00000234420.11	NP_000170.1
FBXO11	NM_001190274.2	c.*1366delA		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.4002-10delT		intron_variant	Intron 9 of 9	1	NM_000179.3	ENSP00000234420.5
FBXO11	ENST00000403359.8	c.*1366delA		downstream_gene_variant		1	NM_001190274.2	ENSP00000384823.4

Frequencies

GnomAD3 genomes AF: 0.276 AC: 38186 AN: 138274 Hom.: 4785 Cov.: 0

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.224

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.261

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.376 AC: 468028 AN: 1243754 Hom.: 866 Cov.: 0 AF XY: 0.378 AC XY: 234567 AN XY: 620164

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

African (AFR) AF: 0.334 AC: 9047 AN: 27092

American (AMR) AF: 0.375 AC: 12828 AN: 34204

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 9451 AN: 23028

East Asian (EAS) AF: 0.425 AC: 13490 AN: 31752

South Asian (SAS) AF: 0.402 AC: 28645 AN: 71168

European-Finnish (FIN) AF: 0.391 AC: 15955 AN: 40838

Middle Eastern (MID) AF: 0.402 AC: 1971 AN: 4898

European-Non Finnish (NFE) AF: 0.372 AC: 356967 AN: 959242

Other (OTH) AF: 0.382 AC: 19674 AN: 51532

⚠️ 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: 0.276 AC: 38212 AN: 138328 Hom.: 4792 Cov.: 0 AF XY: 0.276 AC XY: 18429 AN XY: 66778

African (AFR) AF: 0.302 AC: 11471 AN: 38032

American (AMR) AF: 0.200 AC: 2720 AN: 13588

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1077 AN: 3312

East Asian (EAS) AF: 0.239 AC: 1053 AN: 4404

South Asian (SAS) AF: 0.217 AC: 916 AN: 4224

European-Finnish (FIN) AF: 0.283 AC: 2249 AN: 7956

Middle Eastern (MID) AF: 0.220 AC: 59 AN: 268

European-Non Finnish (NFE) AF: 0.281 AC: 17902 AN: 63776

Other (OTH) AF: 0.263 AC: 500 AN: 1900

Alfa AF: 0.213 Hom.: 174

ClinVar

Significance: Likely benign

Submissions summary: Benign:13

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 55% of patients studied by a panel of primary immunodeficiencies. Number of patients: 52. Only high quality variants are reported. -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

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

- -

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:3

Aug 07, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 05, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 5 Benign:2

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome Benign:2

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: research

Intronic variant with no effect on splicing & MAF 0.01-1% -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 c.4002-10delT variant was not identified in the literature nor was it identified in HGMD, COSMIC, MutDB, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “Zhejiang Colon Cancer Database”, Gene Insight through the Canadian Open Genetics Repository (http://opengenetics.ca/) and UMD databases. The variant was identified in dbSNP (ID: rs267608137) “With likely benign allele, in NHLBI Exome Sequencing Project (Exome Variant Server) in 6 of 8244 Europeans Americans (frequency: 0.0007), and the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 9 of 99520 chromosomes, or 5 individuals from a population of African individuals, 1 from European (Non-Finnish), 1 from Latino, and 2 from South Asian individuals; and none from European (Finnish), East Asian, or Other individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was identified in “InSiGHT Colon Cancer Database” (3X) and in the ClinVar database (classified as likely benign by InSight). The variant was also found to co-occur with a pathogenic MSH6 mutation (c.2348_2349delGT) in 1 individual with endometrial cancer identified from our laboratory increasing the likelihood the c.4002-10delT variant is benign. The c.4002-10delT variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, we lean towards a more benign role for this variant. This variant is classified as benign. -

Breast and/or ovarian cancer Benign:1

Dec 07, 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		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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;