chr2-47801087-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000179.3(MSH6):c.3104G>A(p.Arg1035Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,611,246 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1035L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:2

Conservation

PhyloP100: 7.89

Publications

12 publications found

Variant links:

COSMIC-nc: COSV52282586

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: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 49 uncertain in NM_000179.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.3104G>A	p.Arg1035Gln	missense_variant	Exon 4 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.3104G>A	p.Arg1035Gln	missense_variant	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000282

AC:

AN:

248120

AF XY:

0.0000224

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000445

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000398

AC:

AN:

1459092

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

725732

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33376

American (AMR)

AF:

0.0000227

AC:

AN:

44058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26014

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85688

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000459

AC:

AN:

1111104

Other (OTH)

AF:

0.0000166

AC:

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.0000329

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41426

American (AMR)

AF:

0.000131

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.0000302

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

May 09, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with glutamine at codon 1035 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with prostate cancer (PMID: 26689913). In a large breast cancer case-control study, this variant has been reported in 3/60466 cases and 4/53461 unaffected controls (PMID: 33471991). This variant has been identified in 7/248120 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Mar 17, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R1035Q variant (also known as c.3104G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 3104. The arginine at codon 1035 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a prostate cancer patient from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun. 2015 Dec 22;6:10086). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Jan 23, 2022

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not provided

Uncertain:2

Feb 13, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population, 0.000044 (5/112482 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 35402282 (2022), 35127508 (2022)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in healthy controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Nov 18, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with prostate cancer and in the tumor of an individual with microsatellite unstable colon cancer who also carried an MSH2 pathogenic variant (Lu 2015, Hampel 2018); This variant is associated with the following publications: (PMID: 26689913, 27978560, 29596542) -

Lynch syndrome 5

Uncertain:1Benign:1

Jun 24, 2021

Genetics and Molecular Pathology, SA Pathology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MSH6 c.3104G>A variant is classified as VUS (PP3), and was detected with another somatic pathogenic MSH6 variant. -

Jan 03, 2025

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. -

not specified

Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lynch syndrome

Uncertain: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

Endometrial carcinoma

Uncertain:1

Mar 12, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Jan 15, 2025

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

0.29

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

.;.;T;D;T;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D;D;D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Uncertain

0.74

D;D;D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.7

.;.;.;M;.;.

PhyloP100

7.9

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.2

.;D;.;D;.;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.011

.;D;.;D;.;D

Sift4G

Uncertain

0.035

D;D;D;D;D;D

Polyphen

1.0

.;.;.;D;.;.

Vest4

0.67

MutPred

0.52

.;.;.;Loss of MoRF binding (P = 0.0315);.;.;

MVP

0.96

ClinPred

0.72

GERP RS

4.3

Varity_R

0.85

gMVP

0.79

Mutation Taster

=18/82

disease causing

(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