2-47806751-CTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTT

Position:

• chr2-47806751-CTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000234420.11(MSH6):​c.4002-10del 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 ENST00000234420.11 intron
• Clinical Significance: Likely benign reviewed by expert panel B:13
• Conservation: PhyloP100: -1.08

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 89508.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47806751-CT-C is described in Lovd as [Likely_benign]. Variant chr2-47806751-CT-C is described in Lovd as [Benign]. Variant chr2-47806751-CT-C is described in Lovd as [Benign]. Variant chr2-47806751-CT-C is described in Lovd as [Likely_benign].
• 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/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.4002-10del		intron_variant		ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.4002-10del		intron_variant		1	NM_000179.3	ENSP00000234420	P4

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

Gnomad4 AFR exome AF: 0.334

Gnomad4 AMR exome AF: 0.375

Gnomad4 ASJ exome AF: 0.410

Gnomad4 EAS exome AF: 0.425

Gnomad4 SAS exome AF: 0.402

Gnomad4 FIN exome AF: 0.391

Gnomad4 NFE exome AF: 0.372

Gnomad4 OTH exome AF: 0.382

GnomAD4 genome AF: 0.276 AC: 38212 AN: 138328 Hom.: 4792 Cov.: 0 AF XY: 0.276 AC XY: 18429 AN XY: 66778

Gnomad4 AFR AF: 0.302

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.325

Gnomad4 EAS AF: 0.239

Gnomad4 SAS AF: 0.217

Gnomad4 FIN AF: 0.283

Gnomad4 NFE AF: 0.281

Gnomad4 OTH AF: 0.263

ClinVar

Significance: Likely benign

Submissions summary: Benign:13

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	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. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 05, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2019	- -

Lynch syndrome 5 Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Lynch syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Likely benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Intronic variant with no effect on splicing & MAF 0.01-1% -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Dec 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs59056100; hg19: chr2-48033890;