rs63750523

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 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 (★). ClinVar reports functional evidence for this variant: "SCV000580128: 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" and additional evidence is available in ClinVar. 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000580128: 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).
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.3701_3706dupAACTTG	p.Glu1234_Leu1235dup	disruptive_inframe_insertion	Exon 8 of 10	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.3797_3802dupAACTTG	p.Glu1266_Leu1267dup	disruptive_inframe_insertion	Exon 9 of 11	NP_001393724.1
	MSH6	NM_001406813.1		c.3707_3712dupAACTTG	p.Glu1236_Leu1237dup	disruptive_inframe_insertion	Exon 8 of 10	NP_001393742.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.3701_3706dupAACTTG	p.Glu1234_Leu1235dup	disruptive_inframe_insertion	Exon 8 of 10	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*3048_*3053dupAACTTG		non_coding_transcript_exon	Exon 7 of 9	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000445503.5	TSL:1	n.*3048_*3053dupAACTTG		3_prime_UTR	Exon 7 of 9	ENSP00000405294.1	F8WAX8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Carcinoma of colon (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

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;