NM_000179.3:c.3701_3706dupAACTTG

Variant names:

• chr2-47806256-A-AGAACTT
• rs63750523
• NM_000179.3:c.3701_3706dupAACTTG

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM4 PP3 PP5_Moderate

The NM_000179.3(MSH6):​c.3701_3706dupAACTTG​(p.Glu1234_Leu1235dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A1236A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH6 NM_000179.3 disruptive_inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.49
• Publications: 6 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 46 uncertain in NM_000179.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000179.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 2-47806256-A-AGAACTT is Pathogenic according to our data. Variant chr2-47806256-A-AGAACTT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 428304.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3701_3706dupAACTTG	p.Glu1234_Leu1235dup	disruptive_inframe_insertion	Exon 8 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3701_3706dupAACTTG	p.Glu1234_Leu1235dup	disruptive_inframe_insertion	Exon 8 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Carcinoma of colon Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6, p.Glu1234_Leu1235dup variant was not identified in the literature nor was the variant identified in dbSNP database, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, COSMIC, MutDB, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, ClinVar database, or UMD. The c.3701_3706dupAACTTG variant occurs outside of the splicing consensus sequence and in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing however, this information is not predictive enough to rule out pathogenicity. The residues that are duplicated are conserved in mammals and are part of the DNA mismatch repair protein MutS, C-terminal locus and variants at this position may affect protein function. This variant is an in-frame duplication resulting in the addition of a glutamine and a leucine (Glu and Leu) residue at codon 1234 to 1235; however, the impact of this alteration on MSH6 protein function is not known. This variant has been observed in one family in recessive form in one family with features of biallelic MMR syndrome increasing the likelihood this variant may have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time athough we would lean towards a more pathogenic role for this variant. This variant is classified as predicted pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 28, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3701_3706dupAACTTG variant, located in coding exon 8 of the MSH6 gene, results from a duplication of six nucleotides between positions 3701 and 3706. This results in the duplication of two amino acids, glutamate and leucine, between codons 1234 and 1235. This amino acid region is well conserved in available vertebrate species. This alteration has been reported in the homozygous state in an individual with features of CMMR-D, including a personal history of astrocytoma diagnosed at 9 (Shuen AY et al. J Clin Oncol, 2019 Feb;37:461-470). Structural analysis indicated that this duplication occurs at the interaction interface between the MSH2 protein and MSH6 protein in the ATPase domain. The two inserted amino acids are predicted to alter the protein's structure and the ability for the MSH6 protein to dimerize with the MSH2 protein (Warren JJ et al. Mol. Cell 2007 May;26(4):579-92). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5
Mutation Taster		=55/45	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs63750523; hg19: chr2-48033395;