2-47791154-TTGTGTGTGTGTGTG-TTGTGTGTGTG

Variant names:

• chr2-47791154-TTGTG-T
• rs397839804
• NM_000179.3:c.457+50_457+53delTGTG

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_000179.3(MSH6):​c.457+50_457+53delTGTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000565 in 1,314,244 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). The gene MSH6 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (1 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0750
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Specifications for MSH6 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 2-47791154-TTGTG-T is Benign according to our data. Variant chr2-47791154-TTGTG-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1167597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000385 (58/150558) while in subpopulation SAS AF = 0.00169 (8/4722). AF 95% confidence interval is 0.000842. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.457+50_457+53delTGTG		intron	N/A	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.553+50_553+53delTGTG		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.463+44_463+47delTGTG		intron	N/A	NP_001393742.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.457+32_457+35delTGTG		intron	N/A	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.457+32_457+35delTGTG		intron	N/A	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.457+32_457+35delTGTG		intron	N/A	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.000385 AC: 58 AN: 150456 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000332

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000974

Gnomad SAS AF: 0.00169

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000415

Gnomad OTH AF: 0.000486

GnomAD4 exome AF: 0.000588 AC: 684 AN: 1163686 Hom.: 1 AF XY: 0.000633 AC XY: 370 AN XY: 584630

African (AFR) AF: 0.000759 AC: 21 AN: 27656

American (AMR) AF: 0.000466 AC: 19 AN: 40750

Ashkenazi Jewish (ASJ) AF: 0.000271 AC: 6 AN: 22112

East Asian (EAS) AF: 0.000268 AC: 10 AN: 37268

South Asian (SAS) AF: 0.00191 AC: 148 AN: 77676

European-Finnish (FIN) AF: 0.0000654 AC: 3 AN: 45894

Middle Eastern (MID) AF: 0.000811 AC: 4 AN: 4930

European-Non Finnish (NFE) AF: 0.000523 AC: 449 AN: 857860

Other (OTH) AF: 0.000484 AC: 24 AN: 49540

GnomAD4 genome AF: 0.000385 AC: 58 AN: 150558 Hom.: 0 Cov.: 32 AF XY: 0.000367 AC XY: 27 AN XY: 73516

African (AFR) AF: 0.000267 AC: 11 AN: 41162

American (AMR) AF: 0.000332 AC: 5 AN: 15060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.000977 AC: 5 AN: 5118

South Asian (SAS) AF: 0.00169 AC: 8 AN: 4722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000415 AC: 28 AN: 67470

Other (OTH) AF: 0.000482 AC: 1 AN: 2076

Alfa AF: 0.000834 Hom.: 1

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	MSH6-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.075
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs397839804;

hg19: chr2-48018293;