2-47806751-CTTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTT

Variant summary

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

The NM_000179.3(MSH6):c.4002-10dup 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 0.091 (612 hom., cov: 0)
  • Exomes 𝑓: 0.093 (39 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• 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-C-CT is Benign according to our data. Variant chr2-47806751-C-CT is described in ClinVar as [Likely_benign]. Clinvar id is 801709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.4002-10dup		intron_variant		ENST00000234420.11

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0914 AC: 12644 AN: 138334 Hom.: 611 Cov.: 0

Gnomad AFR AF: 0.0675

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.0788

Gnomad ASJ AF: 0.0822

Gnomad EAS AF: 0.0412

Gnomad SAS AF: 0.0679

Gnomad FIN AF: 0.0605

Gnomad MID AF: 0.0642

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.0839

GnomAD4 exome AF: 0.0927 AC: 119655 AN: 1290418 Hom.: 39 Cov.: 0 AF XY: 0.0905 AC XY: 58332 AN XY: 644382

Gnomad4 AFR exome AF: 0.0543

Gnomad4 AMR exome AF: 0.0516

Gnomad4 ASJ exome AF: 0.0600

Gnomad4 EAS exome AF: 0.0327

Gnomad4 SAS exome AF: 0.0590

Gnomad4 FIN exome AF: 0.0596

Gnomad4 NFE exome AF: 0.103

Gnomad4 OTH exome AF: 0.0820

GnomAD4 genome AF: 0.0914 AC: 12648 AN: 138388 Hom.: 612 Cov.: 0 AF XY: 0.0868 AC XY: 5799 AN XY: 66822

Gnomad4 AFR AF: 0.0675

Gnomad4 AMR AF: 0.0788

Gnomad4 ASJ AF: 0.0822

Gnomad4 EAS AF: 0.0413

Gnomad4 SAS AF: 0.0682

Gnomad4 FIN AF: 0.0605

Gnomad4 NFE AF: 0.118

Gnomad4 OTH AF: 0.0838

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 27, 2023	- -

Lynch syndrome 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 21, 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;