rs1042821

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000179.3(MSH6):c.116G>A(p.Gly39Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,608,126 control chromosomes in the GnomAD database, including 28,241 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.19 ( 2800 hom., cov: 33)

Exomes 𝑓: 0.18 ( 25441 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:28

Conservation

PhyloP100: 1.78

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004319966).

BP6

Variant 2-47783349-G-A is Benign according to our data. Variant chr2-47783349-G-A is described in ClinVar as [Benign]. Clinvar id is 36581.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47783349-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.116G>A	p.Gly39Glu	missense_variant	Exon 1 of 10	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 link	c.116G>A	p.Gly39Glu	missense_variant	Exon 1 of 10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.189

AC:

28705

AN:

152042

Hom.:

2796

Cov.:

show subpopulations

Gnomad AFR

AF:

0.215

Gnomad AMI

AF:

0.253

Gnomad AMR

AF:

0.145

Gnomad ASJ

AF:

0.307

Gnomad EAS

AF:

0.246

Gnomad SAS

AF:

0.207

Gnomad FIN

AF:

0.125

Gnomad MID

AF:

0.226

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.181

GnomAD3 exomes

AF:

0.182

AC:

42088

AN:

231236

Hom.:

4053

AF XY:

0.186

AC XY:

23663

AN XY:

127506

show subpopulations

Gnomad AFR exome

AF:

0.222

Gnomad AMR exome

AF:

0.104

Gnomad ASJ exome

AF:

0.297

Gnomad EAS exome

AF:

0.253

Gnomad SAS exome

AF:

0.212

Gnomad FIN exome

AF:

0.131

Gnomad NFE exome

AF:

0.181

Gnomad OTH exome

AF:

0.191

GnomAD4 exome

AF:

0.184

AC:

267218

AN:

1455968

Hom.:

25441

Cov.:

AF XY:

0.184

AC XY:

133498

AN XY:

724104

show subpopulations

Gnomad4 AFR exome

AF:

0.217

Gnomad4 AMR exome

AF:

0.110

Gnomad4 ASJ exome

AF:

0.300

Gnomad4 EAS exome

AF:

0.283

Gnomad4 SAS exome

AF:

0.212

Gnomad4 FIN exome

AF:

0.132

Gnomad4 NFE exome

AF:

0.178

Gnomad4 OTH exome

AF:

0.199

GnomAD4 genome

AF:

0.189

AC:

28722

AN:

152158

Hom.:

2800

Cov.:

AF XY:

0.188

AC XY:

13976

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.215

Gnomad4 AMR

AF:

0.145

Gnomad4 ASJ

AF:

0.307

Gnomad4 EAS

AF:

0.246

Gnomad4 SAS

AF:

0.207

Gnomad4 FIN

AF:

0.125

Gnomad4 NFE

AF:

0.180

Gnomad4 OTH

AF:

0.184

Alfa

AF:

0.193

Hom.:

962

Bravo

AF:

0.189

TwinsUK

AF:

0.177

AC:

657

ALSPAC

AF:

0.187

AC:

720

ESP6500AA

AF:

0.194

AC:

758

ESP6500EA

AF:

0.172

AC:

1336

ExAC

AF:

0.178

AC:

21019

Asia WGS

AF:

0.248

AC:

862

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:28

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:7

Feb 29, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 29, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gly39Glu in exon 1 of MSH6: This variant is not expected to have clinical signif icance because it has been identified in 17% (1336/7748) of European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/rs1042821). Gly39Glu in exon 1 of MSH6 (rs1042821; a llele frequency = 17%, 1336/7748) ** -

Lynch syndrome 5

Benign:6

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:4

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24622885, 29442465, 28932927, 27153395, 18523027, 19582761, 24689082, 22949387, 19685280, 22703879) -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome

Benign:3

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: research

MAF >1% -

Oct 03, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Oct 27, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 11, 2019

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Nov 04, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 1

Benign:2

Jul 24, 2014

Pathway Genomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 18, 2017

IntelligeneCG

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carcinoma of colon

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Gly39Glu variant has been previously reported in the literature and is recorded in dbSNP as a polymorphism with an average heterozygosity of 0.307+/-0.243 (dbSNP#: rs1042821); this appreciable frequency in different populations of origin increases the likelihood this is a benign variant. In addition, this variant has been identified by our laboratory in at least one individual with a second pathogenic vairiant, increasing the likelihood this variant is benign. In summary, based on the above information, this variant is classified as benign. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast carcinoma

Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.26

.;T

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.73

T;T

MetaRNN

Benign

0.0043

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N

PrimateAI

Uncertain

0.75

PROVEAN

Benign

0.13

N;N

REVEL

Benign

0.16

Sift

Benign

0.12

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.0

.;B

Vest4

0.28

ClinPred

0.016

GERP RS

2.6

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.065

gMVP

0.36

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