rs1042821

chr2-47783349-G-Achr2-47783349-G-Cchr2-47783349-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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 (★★★). 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 NM_000179.3 missense
• Clinical Significance: Benign reviewed by expert panel B:26
• Conservation: PhyloP100: 1.78

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]

ACMG classification

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 NM_000179.3
• 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	UniProt
MSH6	NM_000179.3	c.116G>A	p.Gly39Glu	missense_variant	1/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.116G>A	p.Gly39Glu	missense_variant	1/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28705 AN: 152042 Hom.: 2796 Cov.: 33

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

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.: 33 AF XY: 0.184 AC XY: 133498 AN XY: 724104

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.: 33 AF XY: 0.188 AC XY: 13976 AN XY: 74392

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:26

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 29, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Lynch syndrome 5 Benign:5

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, 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	- -
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. -

Lynch syndrome Benign:3

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

not provided Benign:3

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) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Hereditary cancer-predisposing syndrome Benign:3

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	- -
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. -

Lynch syndrome 1 Benign:2

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

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

Invitae

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	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	18
Dann	Benign	0.84
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.73	T;T
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.75	T
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	T
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

Other links and lift over

dbSNP: rs1042821; hg19: chr2-48010488; COSMIC: COSV52274018; COSMIC: COSV52274018;