2-47803500-ACCC-ACCCC

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS3PP5_Very_Strong

The NM_000179.3(MSH6):c.3261dupC(p.Phe1088LeufsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000565 in 1,610,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000711433: This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1088 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in Lynch syndrome. ACMG/AMP Criteria applied: PP1_Supporting, PS4, PVS1, PS3.". Synonymous variant affecting the same amino acid position (i.e. F1088F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay. The gene MSH6 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

MSH6
NM_000179.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:51O:1

Conservation

PhyloP100: 0.649

Publications

91 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

FBXO11 links:

Genome browser will be placed here

ACMG classification

Specifications for MSH6 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000711433: This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1088 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in Lynch syndrome. ACMG/AMP Criteria applied: PP1_Supporting, PS4, PVS1, PS3.

PP5

Variant 2-47803500-A-AC is Pathogenic according to our data. Variant chr2-47803500-A-AC is described in ClinVar as Pathogenic. ClinVar VariationId is 89364.Status of the report is reviewed_by_expert_panel, 3 stars.

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.3261dupC	p.Phe1088LeufsTer5	frameshift	Exon 5 of 10	NP_000170.1	P52701-1
MSH6	NM_001406795.1		c.3357dupC	p.Phe1120LeufsTer5	frameshift	Exon 6 of 11	NP_001393724.1
MSH6	NM_001406813.1		c.3267dupC	p.Phe1090LeufsTer5	frameshift	Exon 5 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.3261dupC	p.Phe1088LeufsTer5	frameshift	Exon 5 of 10	ENSP00000234420.5	P52701-1
MSH6	ENST00000445503.5	TSL:1	n.*2608dupC		non_coding_transcript_exon	Exon 4 of 9	ENSP00000405294.1	F8WAX8
MSH6	ENST00000445503.5	TSL:1	n.*2608dupC		3_prime_UTR	Exon 4 of 9	ENSP00000405294.1	F8WAX8

Frequencies

GnomAD3 genomes

AF:

0.0000598

AC:

AN:

150380

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000490

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:

0.0000964

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000888

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000641

AC:

AN:

249750

AF XY:

0.0000517

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.0000710

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.0000562

AC:

AN:

1459662

Hom.:

Cov.:

AF XY:

0.0000606

AC XY:

AN XY:

726236

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33448

American (AMR)

AF:

0.0000224

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26114

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.000303

AC:

AN:

52800

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000513

AC:

AN:

1110638

Other (OTH)

AF:

0.0000332

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

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:

0.0000598

AC:

AN:

150380

Hom.:

Cov.:

AF XY:

0.0000682

AC XY:

AN XY:

73328

show subpopulations

African (AFR)

AF:

0.0000490

AC:

AN:

40806

American (AMR)

AF:

0.00

AC:

AN:

14988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4742

European-Finnish (FIN)

AF:

0.0000964

AC:

AN:

10370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000888

AC:

AN:

67594

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

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:

0.000238

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lynch syndrome 5 (13)

not provided (13)

Lynch syndrome (7)

Hereditary cancer-predisposing syndrome (4)

Endometrial carcinoma (2)

Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 (2)

MSH6-related disorder (2)

Breast and/or ovarian cancer (1)

Gastric cancer (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Inherited MMR deficiency (Lynch syndrome) (1)

Inherited polyposis and early onset colorectal cancer - germline testing (1)

Lynch syndrome 1 (1)

Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 (1)

Lynch-like syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.65

Mutation Taster

=0/200

disease causing (ClinVar)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over