2-47805624-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000179.3(MSH6):c.3563G>A(p.Ser1188Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1188T) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:5

Conservation

PhyloP100: 9.36

Publications

4 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 links:

FBXO11 (HGNC:13590): (F-box protein 11) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

FBXO11 Gene-Disease associations (from GenCC):

intellectual developmental disorder with dysmorphic facies and behavioral abnormalities
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

FBXO11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 54 uncertain in NM_000179.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 2-47805624-G-A is Pathogenic according to our data. Variant chr2-47805624-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 89421.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.3563G>A	p.Ser1188Asn	missense_variant	Exon 7 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 link	c.3563G>A	p.Ser1188Asn	missense_variant	Exon 7 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151366

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1451214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722506

African (AFR)

AF:

0.00

AC:

AN:

33278

American (AMR)

AF:

0.00

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26024

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.00

AC:

AN:

85780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102728

Other (OTH)

AF:

0.00

AC:

AN:

59998

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151366

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73864

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41176

American (AMR)

AF:

0.00

AC:

AN:

15188

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67852

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Mar 04, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, this variant has been reported in an individual with colorectal cancer (PMID: 17101317 (2006)). It has also been reported in a Lynch syndrome family where affected individuals were also positive for the MSH2 c.2768T>A (p.Val923Glu) variant (PMID: 21431882 (2011)). In addition, in vitro functional studies have shown that this variant has a deleterious effect on MSH6 protein function (PMIDs: 21431882 (2011), 31965077 (2020)). Based on the available information, this variant is predicted to be likely pathogenic. -

Sep 26, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: deficient MMR activity (PMID: 21431882, 31965077); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (PMID: 21431882, 22495361); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22495361, 23621914, 17101317, 21431882, 30798936, 31965077, 34445333, 17531815, 21120944) -

Lynch syndrome

Pathogenic:1Uncertain:1

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces serine with asparagine at codon 1188 of the MSH6 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Functional studies reported this variant causing deficient in vitro DNA repair activity (PMID: 21431882, 31965077). This variant has been reported in individuals affected with Lynch syndrome-associated disease, and some individual's colorectal cancer tumors were confirmed to display high microsatellite instability and/or loss of MSH6 protein expression via immunohistochemistry analysis (PMID: 17101317, 21431882, 22495361; ClinVar SCV000813288.6). The c.2768T>A, p.V923E variant in the MSH2 gene was also reported in the related individuals affected with colorectal cancer (PMID: 17101317, 21431882, 22495361). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Feb 04, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_SUP; PP3 (Priors 0.74); PS3 (odds path 42.358) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Jul 04, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S1188N variant (also known as c.3563G>A), located in coding exon 7 of the MSH6 gene, results from a G to A substitution at nucleotide position 3563. The serine at codon 1188 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been previously reported in a family meeting Amsterdam criteria for HNPCC/Lynch syndrome and two affected family members that tested positive for this variant had abnormal, but inconsistent immunohistochemistry (IHC) results. In their colorectal tumors, one individual showed high microsatellite instability (MSI-H), absent MSH6, and reduced MSH2 protein expression while the other showed absent MSH2 with reduced MSH6 protein expression (MSI was not determined). Additionally, the family members who carry the MSH6 p.S1188N alteration also carry a variant of uncertain significance in MSH2 (Okkels H et al. Appl. Immunohistochem. Mol. Morphol. 2012 Oct;20:470-7; Kantelinen J et al. Fam. Cancer. 2011 Sep;10:515-20; Ollila S et al. Gastroenterology. 2006 Nov;131:1408-17). In an in vitro functional assay, MSH6 p.S1188N was reported to be completely deficient in mismatch repair compared to wild type (Kantelinen J et al. Fam. Cancer. 2011 Sep;10:515-20). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Jul 19, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces serine with asparagine at codon 1188 of the MSH6 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function. Functional studies reported this variant causing deficient in vitro DNA repair activity (PMID: 21431882, 31965077). This variant has been reported in individuals affected with Lynch syndrome-associated disease (PMID: PMID: 17101317, 21431882, 22495361; ClinVar SCV000813288.6). Two of the related individuals affected with colorectal cancer also carried the c.2768T>A, p.Val923Glu variant in the MSH2 gene that could explain the observed phenotype (PMID: 17101317, 21431882, 22495361). One of these individual's tumor showed high microsatellite instability, reduced MSH2 protein expression, and loss of MSH6 protein expression according to immunohistochemistry, while the other individual's tumor showed loss of MSH2 expression and reduced MSH6 expression, with microsatellite status not determined. It was also reported that another related individual affected with colorectal cancer only carried the MSH2 variant (PMID: 17101317). However, an in vitro mismatch repair assay found that the activity of the MSH2 p.Val923Glu variant was comparable to that of the wild type (PMID: 21431882). The MSH6 p.Ser1188Asn variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Lynch syndrome 5

Pathogenic:1

Aug 24, 2023

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 21431882, 31965077]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Sep 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1188 of the MSH6 protein (p.Ser1188Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 21431882, 22495361; internal data). ClinVar contains an entry for this variant (Variation ID: 89421). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (PMID: 23621914). Experimental studies have shown that this missense change affects MSH6 function (PMID: 21431882, 31965077). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Endometrial carcinoma

Uncertain:1

Nov 28, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

.;.;D;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

.;D;D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.9

.;.;.;H;.

PhyloP100

9.4

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.9

.;D;.;D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

.;D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

.;.;.;D;.

Vest4

0.98

MutPred

0.97

.;.;.;Loss of catalytic residue at S1188 (P = 0.0658);.;

MVP

0.99

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.99

gMVP

0.98

Mutation Taster

=21/79

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over