rs775498550

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP6_Moderate

The NM_000179.3(MSH6):c.146C>A(p.Ala49Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,593,788 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A49T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.145

Publications

1 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 2-47783379-C-A is Benign according to our data. Variant chr2-47783379-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2996818.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.146C>A	p.Ala49Asp	missense_variant	Exon 1 of 10	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.146C>A	p.Ala49Asp	missense_variant	Exon 1 of 10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000489

AC:

AN:

204472

AF XY:

0.00000881

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000326

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441614

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715844

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32586

American (AMR)

AF:

0.0000237

AC:

AN:

42164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25694

East Asian (EAS)

AF:

0.00

AC:

AN:

38692

South Asian (SAS)

AF:

0.00

AC:

AN:

84406

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102212

Other (OTH)

AF:

0.00

AC:

AN:

59518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ExAC

AF:

0.0000173

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Dec 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

0.0011

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

.;T

Eigen

Benign

0.091

Eigen_PC

Benign

0.10

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.75

T;T

M_CAP

Pathogenic

0.99

MetaRNN

Uncertain

0.48

T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

0.81

L;L

PhyloP100

0.14

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.57

N;N

REVEL

Uncertain

0.34

Sift

Benign

0.11

T;D

Sift4G

Benign

0.58

T;T

Polyphen

0.95

.;P

Vest4

0.42

MutPred

0.17

Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);

MVP

0.88

ClinPred

0.84

GERP RS

3.8

PromoterAI

-0.29

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.18

gMVP

0.49

Mutation Taster

=70/30

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over