2-47803553-T-A

Position:

chr2-47803553-T-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000179.3(MSH6):c.3306T>A(p.Thr1102Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0098 in 1,614,072 control chromosomes in the GnomAD database, including 1,342 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.012 ( 112 hom., cov: 32)

Exomes 𝑓: 0.0096 ( 1230 hom. )

Consequence

MSH6
NM_000179.3 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:23

Conservation

PhyloP100: -2.34

Variant links:

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]

MSH6 links:

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 links:

MSH6 (HGNC:):

MSH6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 2-47803553-T-A is Benign according to our data. Variant chr2-47803553-T-A is described in ClinVar as [Benign]. Clinvar id is 36589.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47803553-T-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.34 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3 linkuse as main transcript	c.3306T>A	p.Thr1102Thr	synonymous_variant	5/10	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 linkuse as main transcript	c.3306T>A	p.Thr1102Thr	synonymous_variant	5/10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1753

AN:

152080

Hom.:

112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00710

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00708

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.197

Gnomad SAS

AF:

0.0133

Gnomad FIN

AF:

0.0120

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00163

Gnomad OTH

AF:

0.0125

GnomAD3 exomes

AF:

0.0203

AC:

5099

AN:

251432

Hom.:

380

AF XY:

0.0186

AC XY:

2522

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00800

Gnomad AMR exome

AF:

0.0137

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.203

Gnomad SAS exome

AF:

0.00797

Gnomad FIN exome

AF:

0.0108

Gnomad NFE exome

AF:

0.00171

Gnomad OTH exome

AF:

0.0148

GnomAD4 exome

AF:

0.00962

AC:

14066

AN:

1461874

Hom.:

1230

Cov.:

AF XY:

0.00952

AC XY:

6922

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00672

Gnomad4 AMR exome

AF:

0.0124

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.243

Gnomad4 SAS exome

AF:

0.00851

Gnomad4 FIN exome

AF:

0.0110

Gnomad4 NFE exome

AF:

0.00132

Gnomad4 OTH exome

AF:

0.0135

GnomAD4 genome

AF:

0.0115

AC:

1752

AN:

152198

Hom.:

112

Cov.:

AF XY:

0.0124

AC XY:

926

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00718

Gnomad4 AMR

AF:

0.00707

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.197

Gnomad4 SAS

AF:

0.0133

Gnomad4 FIN

AF:

0.0120

Gnomad4 NFE

AF:

0.00163

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.00337

Hom.:

Bravo

AF:

0.0121

Asia WGS

AF:

0.0930

AC:

323

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.00160

ClinVar

Significance: Benign

Submissions summary: Benign:23

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 09, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:4

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 15, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 07, 2019	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. -

Lynch syndrome 5

Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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	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 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. -

Lynch syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing;curation	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% -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The p.Thr1102Thr variant has been identified in 27 out of 966 proband chromosomes (frequency 0.028) in individuals with breast, prostate and colorectal cancers, however no normal population controls were included in these studies (Chan 1999, Kolodner 1999, Vahteristo 2005, Colley 2005, Damaraju 2006). However, this variant is listed in dbSNP database (ID#: rs2020910) with an average heterozygosity of 0.053+/-0.154, increasing the likelihood that this variant is benign. In addition, this 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. 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

-0.64

CADD

Benign

0.27

DANN

Benign

0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over