2-47791154-TTGTGTGTGTGTG-TTGTGTGTGTGTGTG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_000179.3(MSH6):c.457+52_457+53dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,312,106 control chromosomes in the GnomAD database, including 347 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.036 (295 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (52 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.0650

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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.457+52_457+53dup		intron_variant		ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.457+52_457+53dup		intron_variant		1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.0362 AC: 5452 AN: 150420 Hom.: 294 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.00331

Gnomad SAS AF: 0.00613

Gnomad FIN AF: 0.000678

Gnomad MID AF: 0.0641

Gnomad NFE AF: 0.00405

Gnomad OTH AF: 0.0340

GnomAD4 exome AF: 0.00727 AC: 8447 AN: 1161584 Hom.: 52 Cov.: 15 AF XY: 0.00691 AC XY: 4033 AN XY: 583666

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.0140

Gnomad4 ASJ exome AF: 0.000453

Gnomad4 EAS exome AF: 0.00431

Gnomad4 SAS exome AF: 0.00605

Gnomad4 FIN exome AF: 0.000610

Gnomad4 NFE exome AF: 0.00377

Gnomad4 OTH exome AF: 0.0142

GnomAD4 genome AF: 0.0363 AC: 5458 AN: 150522 Hom.: 295 Cov.: 32 AF XY: 0.0354 AC XY: 2604 AN XY: 73502

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.000291

Gnomad4 EAS AF: 0.00332

Gnomad4 SAS AF: 0.00635

Gnomad4 FIN AF: 0.000678

Gnomad4 NFE AF: 0.00405

Gnomad4 OTH AF: 0.0342

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome 5 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 19, 2016	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397839804; hg19: chr2-48018293;