2-47791136-A-G

Position:

• chr2-47791136-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001406813.1(MSH6):​c.463+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00592 in 1,610,210 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (50 hom.)
• Consequence: MSH6 NM_001406813.1 splice_region, intron
• Clinical Significance: Likely benign reviewed by expert panel B:25
• Conservation: PhyloP100: -0.789

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]

MSH6 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-47791136-A-G is Benign according to our data. Variant chr2-47791136-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 89522.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47791136-A-G is described in Lovd as [Benign]. Variant chr2-47791136-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00453 (689/151930) while in subpopulation SAS AF= 0.0108 (52/4818). AF 95% confidence interval is 0.00845. There are 2 homozygotes in gnomad4. There are 326 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.457+13A>G		intron_variant		ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.457+13A>G		intron_variant		1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.00454 AC: 689 AN: 151812 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000948

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00556

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00707

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00521 AC: 1308 AN: 250876 Hom.: 8 AF XY: 0.00573 AC XY: 778 AN XY: 135702

Gnomad AFR exome AF: 0.000806

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0103

Gnomad FIN exome AF: 0.00578

Gnomad NFE exome AF: 0.00657

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00606 AC: 8841 AN: 1458280 Hom.: 50 Cov.: 31 AF XY: 0.00627 AC XY: 4553 AN XY: 725736

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0105

Gnomad4 FIN exome AF: 0.00554

Gnomad4 NFE exome AF: 0.00650

Gnomad4 OTH exome AF: 0.00423

GnomAD4 genome AF: 0.00453 AC: 689 AN: 151930 Hom.: 2 Cov.: 33 AF XY: 0.00439 AC XY: 326 AN XY: 74316

Gnomad4 AFR AF: 0.000946

Gnomad4 AMR AF: 0.00295

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.00556

Gnomad4 NFE AF: 0.00707

Gnomad4 OTH AF: 0.00333

Alfa AF: 0.00599 Hom.: 1

Bravo AF: 0.00350

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:25

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 25, 2019	- -

Lynch syndrome 5 Benign:6

Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 22, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Oct 07, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Dec 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 06, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	MSH6: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 22, 2021

- -

Carcinoma of colon Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The c.457+13A>G variant has been previously reported in the literature in individuals with CRC (8/295 chromosomes) but the frequency in controls did not differ significantly from the cases tested (6/185 chromosomes) (Peterlongo_2003_14520694, Woods_2005_16203774). This variant was listed in dbSNP (rs1800933) 'with untested allele' and reported from the 1000 genomes 4 times (MAF of 0.002) The exome variant server reported this variant in a European cohort with the following frequency increasing the likelihood this variant does not have clinical significance: G=54/A=8546. Further, this variant does not occur within the splicing consensus sequence increasing the likelihood this variant does not have clinical significance. -

Lynch syndrome Benign:1

Likely benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability 0.001-0.049 -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1800933; hg19: chr2-48018275; COSMIC: COSV104579408; COSMIC: COSV104579408;