2-47806751-CTTTTTTTTTTTTTTT-CTTTTTTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000179.3(MSH6):c.4002-11_4002-10del 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

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 -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 id is 89509.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=1}. Variant chr2-47806751-CTT-C is described in Lovd as [Benign]. Variant chr2-47806751-CTT-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.4002-11_4002-10del		intron_variant		ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.4002-11_4002-10del		intron_variant		1	NM_000179.3	P4

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

Gnomad4 AFR exome AF: 0.0568

Gnomad4 AMR exome AF: 0.0478

Gnomad4 ASJ exome AF: 0.0707

Gnomad4 EAS exome AF: 0.0549

Gnomad4 SAS exome AF: 0.0492

Gnomad4 FIN exome AF: 0.0678

Gnomad4 NFE exome AF: 0.0558

Gnomad4 OTH exome AF: 0.0550

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

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.00272

Gnomad4 ASJ AF: 0.00241

Gnomad4 EAS AF: 0.00295

Gnomad4 SAS AF: 0.00686

Gnomad4 FIN AF: 0.00416

Gnomad4 NFE AF: 0.00483

Gnomad4 OTH AF: 0.00264

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

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	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. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 06, 2023	- -

Lynch syndrome 5 Benign:1

Likely 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

Apr 22, 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;