chr2-47798625-C-T

Position:

• chr2-47798625-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001281493.2(MSH6):​c.-265C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0912 in 1,610,204 control chromosomes in the GnomAD database, including 7,851 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.072 (550 hom., cov: 32)
  • Exomes 𝑓: 0.093 (7301 hom.)
• Consequence: MSH6 NM_001281493.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel B:24
• Conservation: PhyloP100: -2.00

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=-0.82).
• BP6: Variant 2-47798625-C-T is Benign according to our data. Variant chr2-47798625-C-T is described in ClinVar as [Benign]. Clinvar id is 36599.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47798625-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.642C>T	p.Tyr214Tyr	synonymous_variant	4/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.642C>T	p.Tyr214Tyr	synonymous_variant	4/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10921 AN: 151930 Hom.: 550 Cov.: 32

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.0451

Gnomad AMR AF: 0.0485

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0727

GnomAD3 exomes AF: 0.0711 AC: 17523 AN: 246622 Hom.: 955 AF XY: 0.0710 AC XY: 9483 AN XY: 133640

Gnomad AFR exome AF: 0.0168

Gnomad AMR exome AF: 0.0336

Gnomad ASJ exome AF: 0.0376

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.0168

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.0670

GnomAD4 exome AF: 0.0932 AC: 135926 AN: 1458156 Hom.: 7301 Cov.: 34 AF XY: 0.0909 AC XY: 65945 AN XY: 725442

Gnomad4 AFR exome AF: 0.0152

Gnomad4 AMR exome AF: 0.0350

Gnomad4 ASJ exome AF: 0.0390

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0179

Gnomad4 FIN exome AF: 0.145

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.0778

GnomAD4 genome AF: 0.0718 AC: 10923 AN: 152048 Hom.: 550 Cov.: 32 AF XY: 0.0713 AC XY: 5296 AN XY: 74304

Gnomad4 AFR AF: 0.0198

Gnomad4 AMR AF: 0.0485

Gnomad4 ASJ AF: 0.0363

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.0714

Alfa AF: 0.0921 Hom.: 428

Bravo AF: 0.0614

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.0940

EpiControl AF: 0.0920

ClinVar

Significance: Benign

Submissions summary: Benign:24

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 22, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 21, 2011	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
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+	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Lynch syndrome 5 Benign:4

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Hereditary cancer-predisposing syndrome Benign:4

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, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 27, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2022	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27884173, 12547705, 24689082, 23588873) -

Lynch syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -

Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 13, 2021

- -

Carcinoma of colon Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Tyr214Tyr variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located near a splice junction. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs1800937) with a global minor allele frequency (MAF) of 0.050, being identified in varying frequencies in various ethnic groups from the HapMap project. It has been reported in the literature in 69/1520 proband chromosomes of individuals from HNPCC and HNPCC-like families, as well as in breast cancer families with colorectal and/ or endometrial cancer. It was also reported in 22/1336 control chromosomes evaluated (Charames_2000_11153917, de Abajo_2005_16270383, Dovrat_2005_16341805, Hendriks_2003_12547705, Kolodner_1999_10537275, Perez-Cabornero_2009_19250818, Peterlongo_2003_14520694, Plaschke_2000_10699937, Vahteristo_2005_15805151, Verma_1999_10507723). In addition, the variant was also identified in the UMD database (x66) as a neutral alteration, as well as in the InSiGHT and Exome Server databases. In summary, based on the above information, this variant is classified as Benign. -

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	-0.82
CADD	Benign	0.23
DANN	Benign	0.92
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2

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: rs1800937; hg19: chr2-48025764; COSMIC: COSV52279626; COSMIC: COSV52279626;