NM_000179.3:c.187T>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS1

The NM_000179.3(MSH6):c.187T>C(p.Ser63Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000344 in 1,510,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S63C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:6

Conservation

PhyloP100: -0.141

Publications

6 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: ClinGen, G2P, Orphanet
Lynch syndrome 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26435593).

BP6

Variant 2-47783420-T-C is Benign according to our data. Variant chr2-47783420-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220796.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000211 (32/151968) while in subpopulation AFR AF = 0.000772 (32/41446). AF 95% confidence interval is 0.000562. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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	UniProt
MSH6	NM_000179.3	MANE Select	c.187T>C	p.Ser63Pro	missense	Exon 1 of 10	NP_000170.1	P52701-1
MSH6	NM_001406795.1		c.187T>C	p.Ser63Pro	missense	Exon 1 of 11	NP_001393724.1
MSH6	NM_001406813.1		c.187T>C	p.Ser63Pro	missense	Exon 1 of 10	NP_001393742.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MSH6	ENST00000234420.11	TSL:1 MANE Select	c.187T>C	p.Ser63Pro	missense	Exon 1 of 10	ENSP00000234420.5	P52701-1
MSH6	ENST00000445503.5	TSL:1	n.187T>C		non_coding_transcript_exon	Exon 1 of 9	ENSP00000405294.1	F8WAX8
MSH6	ENST00000936511.1		c.187T>C	p.Ser63Pro	missense	Exon 1 of 10	ENSP00000606570.1

Frequencies

GnomAD3 genomes

AF:

0.000211

AC:

AN:

151856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000774

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00000875

AC:

AN:

114340

AF XY:

0.0000156

show subpopulations

Gnomad AFR exome

AF:

0.000237

Gnomad AMR exome

AF:

0.00

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:

0.0000147

AC:

AN:

1358776

Hom.:

Cov.:

AF XY:

0.0000120

AC XY:

AN XY:

668820

show subpopulations

African (AFR)

AF:

0.000637

AC:

AN:

28256

American (AMR)

AF:

0.00

AC:

AN:

27568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22558

East Asian (EAS)

AF:

0.00

AC:

AN:

33914

South Asian (SAS)

AF:

0.00

AC:

AN:

74660

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5456

European-Non Finnish (NFE)

AF:

9.40e-7

AC:

AN:

1063496

Other (OTH)

AF:

0.0000179

AC:

AN:

55834

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000211

AC:

AN:

151968

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.000772

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5088

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000200

ExAC

AF:

0.00000980

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (3)

Lynch syndrome 5 (2)

not specified (2)

Endometrial carcinoma (1)

Endometrial carcinoma;C1833477:Lynch syndrome 5;C5399763:Mismatch repair cancer syndrome 1 (1)

Hereditary nonpolyposis colorectal neoplasms (1)

MSH6-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.018

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.27

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.64

M_CAP

Pathogenic

0.88

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.81

PhyloP100

-0.14

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.82

REVEL

Benign

0.28

Sift

Benign

0.14

Sift4G

Benign

0.27

Polyphen

0.38

Vest4

0.33

MVP

0.74

ClinPred

0.082

GERP RS

0.20

PromoterAI

-0.056

Neutral

(source)

Varity_R

0.21

gMVP

0.31

Mutation Taster

=90/10

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over