2-47783075-C-T

Variant names:

Variant summary

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

The ENST00000652107.1(MSH6):c.-37-7852C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0899 in 862,978 control chromosomes in the GnomAD database, including 4,218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.073 ( 573 hom., cov: 33)

Exomes 𝑓: 0.094 ( 3645 hom. )

Consequence

MSH6
ENST00000652107.1 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:4

Conservation

PhyloP100: -0.469

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=-0.79).

BP6

Variant 2-47783075-C-T is Benign according to our data. Variant chr2-47783075-C-T is described in ClinVar as [Benign]. Clinvar id is 89158.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.-159C>T		upstream_gene_variant		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.-159C>T		upstream_gene_variant		1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.0726

AC:

11022

AN:

151740

Hom.:

573

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0202

Gnomad AMI

AF:

0.0450

Gnomad AMR

AF:

0.0490

Gnomad ASJ

AF:

0.0366

Gnomad EAS

AF:

0.000583

Gnomad SAS

AF:

0.0135

Gnomad FIN

AF:

0.157

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.0729

GnomAD4 exome

AF:

0.0935

AC:

66524

AN:

711130

Hom.:

3645

Cov.:

AF XY:

0.0905

AC XY:

32500

AN XY:

359156

show subpopulations

African (AFR)

AF:

0.0167

AC:

231

AN:

13830

American (AMR)

AF:

0.0476

AC:

477

AN:

10012

Ashkenazi Jewish (ASJ)

AF:

0.0406

AC:

563

AN:

13862

East Asian (EAS)

AF:

0.000160

AC:

AN:

25008

South Asian (SAS)

AF:

0.0191

AC:

858

AN:

44824

European-Finnish (FIN)

AF:

0.147

AC:

4402

AN:

29984

Middle Eastern (MID)

AF:

0.0225

AC:

AN:

2488

European-Non Finnish (NFE)

AF:

0.107

AC:

57343

AN:

537738

Other (OTH)

AF:

0.0776

AC:

2590

AN:

33384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

2958

5916

8873

11831

14789

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0726

AC:

11024

AN:

151848

Hom.:

573

Cov.:

AF XY:

0.0721

AC XY:

5352

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.0202

AC:

838

AN:

41506

American (AMR)

AF:

0.0489

AC:

747

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.0366

AC:

127

AN:

3466

East Asian (EAS)

AF:

0.000584

AC:

AN:

5134

South Asian (SAS)

AF:

0.0139

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.157

AC:

1645

AN:

10488

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.109

AC:

7402

AN:

67852

Other (OTH)

AF:

0.0716

AC:

151

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

512

1024

1537

2049

2561

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0817

Hom.:

179

Bravo

AF:

0.0621

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Lynch syndrome

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:research

MAF >1% -

not provided

Benign:2

Jun 23, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

7.7

(source)

DANN

Benign

0.91

PhyloP100

-0.47

PromoterAI

0.13

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-47783075-C-T

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