chr2-47800903-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP6

The NM_000179.3(MSH6):c.2920A>G(p.Arg974Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000314 in 1,592,238 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. R974W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.11

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: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 45 uncertain in NM_000179.3

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 2-47800903-A-G is Benign according to our data. Variant chr2-47800903-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 483777.

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
MSH6	NM_000179.3	MANE Select	c.2920A>G	p.Arg974Gly	missense	Exon 4 of 10	NP_000170.1
MSH6	NM_001406795.1		c.3016A>G	p.Arg1006Gly	missense	Exon 5 of 11	NP_001393724.1
MSH6	NM_001406813.1		c.2926A>G	p.Arg976Gly	missense	Exon 4 of 10	NP_001393742.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MSH6	ENST00000234420.11	TSL:1 MANE Select	c.2920A>G	p.Arg974Gly	missense	Exon 4 of 10	ENSP00000234420.5
MSH6	ENST00000445503.5	TSL:1	n.*2267A>G		non_coding_transcript_exon	Exon 3 of 9	ENSP00000405294.1
MSH6	ENST00000445503.5	TSL:1	n.*2267A>G		3_prime_UTR	Exon 3 of 9	ENSP00000405294.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00000852

AC:

AN:

234792

AF XY:

0.0000158

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000184

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000278

AC:

AN:

1439982

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

714318

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32322

American (AMR)

AF:

0.00

AC:

AN:

40198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25048

East Asian (EAS)

AF:

0.00

AC:

AN:

39454

South Asian (SAS)

AF:

0.00

AC:

AN:

82728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53024

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.00000363

AC:

AN:

1102248

Other (OTH)

AF:

0.00

AC:

AN:

59322

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:

152256

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 25, 2017

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Uncertain:1

Jun 09, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R974G variant (also known as c.2920A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2920. The arginine at codon 974 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Sep 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.39

MetaRNN

Uncertain

0.62

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

1.3

PhyloP100

3.1

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0040

Polyphen

0.87

Vest4

0.51

MutPred

0.72

Loss of sheet (P = 0.0315)

MVP

0.93

ClinPred

0.96

GERP RS

4.4

Varity_R

0.87

gMVP

0.67

Mutation Taster

=56/44

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over