rs55927047

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000179.3(MSH6):c.260+22C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,391,608 control chromosomes in the GnomAD database, including 21,647 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.13 ( 1551 hom., cov: 30)

Exomes 𝑓: 0.17 ( 20096 hom. )

Consequence

MSH6
NM_000179.3 intron

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:10

Conservation

PhyloP100: -2.21

Publications

9 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 2-47783515-C-G is Benign according to our data. Variant chr2-47783515-C-G is described in ClinVar as Benign. ClinVar VariationId is 89295.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.260+22C>G		intron_variant	Intron 1 of 9	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 link	c.260+22C>G		intron_variant	Intron 1 of 9	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes

AF:

0.130

AC:

19187

AN:

148068

Hom.:

1553

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0551

Gnomad AMI

AF:

0.167

Gnomad AMR

AF:

0.126

Gnomad ASJ

AF:

0.157

Gnomad EAS

AF:

0.00103

Gnomad SAS

AF:

0.0614

Gnomad FIN

AF:

0.124

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.187

Gnomad OTH

AF:

0.150

GnomAD2 exomes

AF:

0.139

AC:

4248

AN:

30570

AF XY:

0.142

show subpopulations

Gnomad AFR exome

AF:

0.0588

Gnomad AMR exome

AF:

0.120

Gnomad ASJ exome

AF:

0.177

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.127

Gnomad NFE exome

AF:

0.206

Gnomad OTH exome

AF:

0.148

GnomAD4 exome

AF:

0.175

AC:

217153

AN:

1243430

Hom.:

20096

Cov.:

AF XY:

0.173

AC XY:

103601

AN XY:

600298

show subpopulations

African (AFR)

AF:

0.0432

AC:

1039

AN:

24050

American (AMR)

AF:

0.113

AC:

1672

AN:

14756

Ashkenazi Jewish (ASJ)

AF:

0.163

AC:

2816

AN:

17300

East Asian (EAS)

AF:

0.000378

AC:

AN:

29078

South Asian (SAS)

AF:

0.0785

AC:

4394

AN:

55980

European-Finnish (FIN)

AF:

0.122

AC:

5085

AN:

41792

Middle Eastern (MID)

AF:

0.170

AC:

683

AN:

4024

European-Non Finnish (NFE)

AF:

0.192

AC:

193416

AN:

1005430

Other (OTH)

AF:

0.158

AC:

8037

AN:

51020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

8940

17880

26819

35759

44699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7146

14292

21438

28584

35730

<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:

0.129

AC:

19185

AN:

148178

Hom.:

1551

Cov.:

AF XY:

0.126

AC XY:

9088

AN XY:

72358

show subpopulations

African (AFR)

AF:

0.0552

AC:

2216

AN:

40134

American (AMR)

AF:

0.126

AC:

1884

AN:

15006

Ashkenazi Jewish (ASJ)

AF:

0.157

AC:

537

AN:

3430

East Asian (EAS)

AF:

0.00104

AC:

AN:

4822

South Asian (SAS)

AF:

0.0614

AC:

283

AN:

4610

European-Finnish (FIN)

AF:

0.124

AC:

1279

AN:

10304

Middle Eastern (MID)

AF:

0.176

AC:

AN:

256

European-Non Finnish (NFE)

AF:

0.187

AC:

12491

AN:

66720

Other (OTH)

AF:

0.148

AC:

302

AN:

2042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

817

1633

2450

3266

4083

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

212

424

636

848

1060

<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:

0.140

Hom.:

227

Bravo

AF:

0.127

Asia WGS

AF:

0.0410

AC:

146

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

Jul 02, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 31% of patients studied by a panel of primary immunodeficiencies. Number of patients: 29. Only high quality variants are reported. -

not provided

Uncertain:1Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Lynch syndrome 5

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lynch syndrome

Benign:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:research

MAF >1% -

Hereditary cancer-predisposing syndrome

Benign:1

Jul 12, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

8.6

(source)

DANN

Benign

0.74

PhyloP100

-2.2

PromoterAI

0.018

Neutral

(source)

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over