Genetic Variant NM_000179.3:c.116G>A (chr2-47783349-G-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G39R) has been classified as Likely 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:30

Conservation

PhyloP100: 1.78

Publications

122 publications found

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 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
Lynch syndrome 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
mismatch repair cancer syndrome 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
ovarian cancer
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
Muir-Torre syndrome
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
breast cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MSH6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 22 benign, 51 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 VariationId is 36581.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000179.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MSH6	NM_000179.3	MANE Select	c.116G>A	p.Gly39Glu	missense	Exon 1 of 10	NP_000170.1
MSH6	NM_001406795.1		c.116G>A	p.Gly39Glu	missense	Exon 1 of 11	NP_001393724.1
MSH6	NM_001406813.1		c.116G>A	p.Gly39Glu	missense	Exon 1 of 10	NP_001393742.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MSH6	ENST00000234420.11	TSL:1 MANE Select	c.116G>A	p.Gly39Glu	missense	Exon 1 of 10	ENSP00000234420.5
MSH6	ENST00000445503.5	TSL:1	n.116G>A		non_coding_transcript_exon	Exon 1 of 9	ENSP00000405294.1
MSH6	ENST00000936511.1		c.116G>A	p.Gly39Glu	missense	Exon 1 of 10	ENSP00000606570.1

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

GnomAD2 exomes

AF:

0.182

AC:

42088

AN:

231236

AF XY:

0.186

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 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

African (AFR)

AF:

0.217

AC:

7200

AN:

33154

American (AMR)

AF:

0.110

AC:

4884

AN:

44240

Ashkenazi Jewish (ASJ)

AF:

0.300

AC:

7786

AN:

25960

East Asian (EAS)

AF:

0.283

AC:

11168

AN:

39462

South Asian (SAS)

AF:

0.212

AC:

18195

AN:

85720

European-Finnish (FIN)

AF:

0.132

AC:

6858

AN:

51876

Middle Eastern (MID)

AF:

0.251

AC:

1442

AN:

5744

European-Non Finnish (NFE)

AF:

0.178

AC:

197694

AN:

1109648

Other (OTH)

AF:

0.199

AC:

11991

AN:

60164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

12844

25688

38532

51376

64220

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7124

14248

21372

28496

35620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.189

AC:

28722

AN:

152158

Hom.:

2800

Cov.:

AF XY:

0.188

AC XY:

13976

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.215

AC:

8935

AN:

41536

American (AMR)

AF:

0.145

AC:

2224

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.307

AC:

1066

AN:

3472

East Asian (EAS)

AF:

0.246

AC:

1262

AN:

5134

South Asian (SAS)

AF:

0.207

AC:

996

AN:

4818

European-Finnish (FIN)

AF:

0.125

AC:

1322

AN:

10618

Middle Eastern (MID)

AF:

0.219

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.180

AC:

12235

AN:

67964

Other (OTH)

AF:

0.184

AC:

388

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1224

2447

3671

4894

6118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

322

644

966

1288

1610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lynch syndrome 5 (7)

not specified (7)

Hereditary cancer-predisposing syndrome (4)

not provided (4)

Lynch syndrome (3)

Lynch syndrome 1 (2)

Breast carcinoma (1)

Carcinoma of colon (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.26

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0043

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

1.8

PrimateAI

Uncertain

0.75

PROVEAN

Benign

0.13

REVEL

Benign

0.16

Sift

Benign

0.12

Sift4G

Benign

0.53

Polyphen

0.0

Vest4

0.28

ClinPred

0.016

GERP RS

2.6

PromoterAI

0.046

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.065

gMVP

0.36

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over