rs1042821

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000234420.11(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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G39A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.19 ( 2800 hom., cov: 33)

Exomes 𝑓: 0.18 ( 25441 hom. )

Consequence

MSH6
ENST00000234420.11 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:27

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 -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 17 uncertain in ENST00000234420.11

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/exons	MANE	Protein	UniProt
MSH6	NM_000179.3 linkuse as main transcript	c.116G>A	p.Gly39Glu	missense_variant	1/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 linkuse as main transcript	c.116G>A	p.Gly39Glu	missense_variant	1/10	1	NM_000179.3	ENSP00000234420	P4	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:27

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2008	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) ** -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 29, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
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+	-	- -

Lynch syndrome 5

Benign:5

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:4

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 30, 2023	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24622885, 29442465, 28932927, 27153395, 18523027, 19582761, 24689082, 22949387, 19685280, 22703879) -

Lynch syndrome

Benign:3

Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 02, 2011	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 03, 2024	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 27, 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	curation	Sema4, Sema4	Dec 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 04, 2014	- -

Lynch syndrome 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	IntelligeneCG	Aug 18, 2017	- -
Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Breast carcinoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

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

MutationTaster

Benign

1.0

P;P

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