rs2020906

Positions:

• chr2-47806945-T-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000179.3(MSH6):​c.*85T>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00729 in 1,036,700 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0062 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0075 (37 hom.)
• Consequence: MSH6 NM_000179.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 3.97

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-47806945-T-A is Benign according to our data. Variant chr2-47806945-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89155.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=1, Uncertain_significance=1}. Variant chr2-47806945-T-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00624 (950/152148) while in subpopulation NFE AF= 0.0092 (625/67946). AF 95% confidence interval is 0.0086. There are 4 homozygotes in gnomad4. There are 524 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.*85T>A		3_prime_UTR_variant	10/10	ENST00000234420.11
FBXO11	NM_001190274.2	c.*1173A>T		3_prime_UTR_variant	23/23	ENST00000403359.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.*85T>A		3_prime_UTR_variant	10/10	1	NM_000179.3	P4
FBXO11	ENST00000403359.8	c.*1173A>T		3_prime_UTR_variant	23/23	1	NM_001190274.2

Frequencies

GnomAD3 genomes AF: 0.00625 AC: 950 AN: 152030 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00920

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00747 AC: 6612 AN: 884552 Hom.: 37 Cov.: 12 AF XY: 0.00720 AC XY: 3331 AN XY: 462708

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.000920

Gnomad4 ASJ exome AF: 0.00179

Gnomad4 EAS exome AF: 0.000874

Gnomad4 SAS exome AF: 0.00287

Gnomad4 FIN exome AF: 0.0162

Gnomad4 NFE exome AF: 0.00868

Gnomad4 OTH exome AF: 0.00586

GnomAD4 genome AF: 0.00624 AC: 950 AN: 152148 Hom.: 4 Cov.: 31 AF XY: 0.00704 AC XY: 524 AN XY: 74388

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0214

Gnomad4 NFE AF: 0.00920

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00923 Hom.: 0

Bravo AF: 0.00466

Asia WGS AF: 0.000867 AC: 3 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 12, 2017	- -

Lynch syndrome 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

MSH6: BS1, BS2 -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2023

- -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Oct 22, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	10
DANN	Benign	0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs2020906; hg19: chr2-48034084;