2-47791154-TTGTGTGTGTGTGTG-TTGTGTGTGTGTGTGTG

Variant names:

• chr2-47791154-T-TTG
• rs397839804
• NM_000179.3:c.457+52_457+53dupTG

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.457+52_457+53dupTG 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (295 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (52 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 0.0650
• 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 2-47791154-T-TTG is Benign according to our data. Variant chr2-47791154-T-TTG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 89527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000179.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.457+52_457+53dupTG		intron	N/A	NP_000170.1
	MSH6	NM_001406795.1		c.553+52_553+53dupTG		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.463+46_463+47dupTG		intron	N/A	NP_001393742.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.457+31_457+32insTG		intron	N/A	ENSP00000234420.5
	MSH6	ENST00000445503.5	TSL:1	n.457+31_457+32insTG		intron	N/A	ENSP00000405294.1
	MSH6	ENST00000700002.1		c.457+31_457+32insTG		intron	N/A	ENSP00000514750.1

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

African (AFR) AF: 0.113 AC: 3134 AN: 27634

American (AMR) AF: 0.0140 AC: 569 AN: 40712

Ashkenazi Jewish (ASJ) AF: 0.000453 AC: 10 AN: 22062

East Asian (EAS) AF: 0.00431 AC: 160 AN: 37114

South Asian (SAS) AF: 0.00605 AC: 469 AN: 77538

European-Finnish (FIN) AF: 0.000610 AC: 28 AN: 45894

Middle Eastern (MID) AF: 0.0309 AC: 152 AN: 4918

European-Non Finnish (NFE) AF: 0.00377 AC: 3224 AN: 856244

Other (OTH) AF: 0.0142 AC: 701 AN: 49468

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

African (AFR) AF: 0.116 AC: 4759 AN: 41126

American (AMR) AF: 0.0186 AC: 280 AN: 15062

Ashkenazi Jewish (ASJ) AF: 0.000291 AC: 1 AN: 3434

East Asian (EAS) AF: 0.00332 AC: 17 AN: 5118

South Asian (SAS) AF: 0.00635 AC: 30 AN: 4722

European-Finnish (FIN) AF: 0.000678 AC: 7 AN: 10320

Middle Eastern (MID) AF: 0.0690 AC: 20 AN: 290

European-Non Finnish (NFE) AF: 0.00405 AC: 273 AN: 67466

Other (OTH) AF: 0.0342 AC: 71 AN: 2076

Alfa AF: 0.00330 Hom.: 1

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 5 Uncertain:1 Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 19, 2016

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

not specified Benign:1

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:1

Aug 30, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.065
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs397839804; hg19: chr2-48018293; COSMIC: COSV52285463; COSMIC: COSV52285463;