rs267608077

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000179.3(MSH6):c.1135_1139delAGAGA(p.Arg379fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000274 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R379R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MSH6
NM_000179.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:22U:1

Conservation

PhyloP100: 5.86

Publications

12 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: Pathogenic. The variant received 18 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-47799111-AAAGAG-A is Pathogenic according to our data. Variant chr2-47799111-AAAGAG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 89174.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.1135_1139delAGAGA	p.Arg379fs	frameshift_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.1135_1139delAGAGA	p.Arg379fs	frameshift_variant	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250986

AF XY:

0.00

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461882

Hom.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:6Uncertain:1

Feb 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Feb 17, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Kets et al., 2006; Frolova et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 28888541, 17117178, 17453009, 25617771, 26681312, 26845104, 27064304, 28152038, 28452373, 26689913, 28514183, 29625052, 30787465, 30013564) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 25, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This nonsense variant causes the premature termination of MSH6 protein synthesis. In the published literature, it has been reported in individuals affected with endometrial, ovarian, and breast cancer (PMID: 17117178 (2006), 17453009 (2007), 25617771 (2015), 26681312 (2015)), as well as in a compound heterozygous individual with CMMRD syndrome (PMID: 30013564 (2018)). Based on the available information, this variant is classified as pathogenic. -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Lynch syndrome 5

Pathogenic:5

Mar 03, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 11, 2023

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Aug 01, 2022

Human Genetics Bochum, Ruhr University Bochum

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG criteria used to clasify this variant: PVS1, PM2 -

Aug 19, 2016

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PVS1,PM2_SUP,PM3_SUP,PP4 -

Lynch syndrome

Pathogenic:4

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 22, 2023

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1135_1139del (p.Arg379*) variant in the MSH6 gene, that encodes for mutS homolog 6, introduces a premature translation termination codon resulting in an absent or disrupted protein product. The variant has been reported in several individuals (>10) affected with endometrial, ovarian, breast, colorectal cancers and Lynch syndrome (PMID:17117178, 17453009, 25617771, 28452373, 28514183, 26681312). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 9354786, 11709755, 20028993, 25318681). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 29345684, 28514183) and by several ClinVar submitters (ClinVar ID: 418928, 1172098, 183736, 89184). This variant is found to be rare (1/250986; 0.000003984) in the general population database, gnomAD and interpreted as pathogenic by several ClinVar submitters including the expert panel (ClinVar ID: 89174). Therefore, the c.1135_1139del (p.Arg379*) variant in the MSH6 gene is classified as pathogenic. -

Aug 31, 2024

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:research

Coding sequence variation resulting in a stop codon -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Mar 31, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1135_1139delAGAGA pathogenic mutation (also known as p.R379*), located in coding exon 4 of the MSH6 gene, results from a deletion of 5 nucleotides at nucleotide positions 1135 to 1139. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been previously identified in an individual diagnosed with Lynch syndrome (Kets CM et al. Br. J. Cancer. 2006 Dec 18;95(12): 1678-82) and in a patient with CMMRD (Tesch VK et al. Front Immunol. 2018 Jul;9:1506). It has also been reported in an individual with breast cancer at age 60, as well as endometrial and ovarian cancer at age 61, whose endometrial tumor showed loss of MSH2 on IHC (Frolova AI et al. Gynecol. Oncol. 2015 Apr;137:7-13). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Jul 08, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant deletes 5 nucleotides in exon 4 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in individuals affected with colorectal cancer, endometrial and/or ovarian cancer (PMID: 17117178, 17453009, 26845104, 25617771), as well as cervical cancer (PMID: 26681312). Tumors from affected individuals have demonstrated high microsatellite instability and/or loss of MSH6 protein via immunohistochemistry (PMID: 17117178, 17453009, 26845104, 37318702). This variant has also been observed in trans with another MSH6 variant in an individual affected with constitutional mismatch repair deficiency (PMID: 30013564). This variant has been identified in 1/250986 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Feb 20, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PM2_Supporting, PP1, PP4_Strong c.1135_1139del, located in exon 4 of the MSH6 gene, consists on the deletion of 5 nucleotides, causing a translational frameshift with a predicted alternate stop codon, p.(Arg379*). This alteration is expected to result in loss of function by premature protein truncation and nonsense-mediated mRNA decay (PVS1). The SpliceAI algorithm predicts no significant impact on splicing. This variant is found in 1/267851 alleles at a frequency of 0,0003% in the gnomAD v2.1.1 database, non-cancer dataset (PM2_supporting). To our knowledge, no well-established functional studies have been reported for this variant. This variant cosegregates with the disease (2 meiosis, internal data) (PP1). Furthermore, this variant has been reported in colorectal and endometrial cancer-affected individuals with isolated loss of MSH6 expression by IHC (PMID: 17117178, internal data) (PP4_Strong). This variant has been reported in the ClinVar database (17x pathogenic, 1x likely pathogenic, 1x uncertain significance), in the LOVD database (5x pathogenic), and has been classified by InSiGHT as pathogenic. Based on currently available information, the variant c.1135_1139del should be considered a pathogenic variant according to ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 1.0.0. -

Hereditary nonpolyposis colon cancer

Pathogenic:1

Feb 21, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MSH6 c.1135_1139delAGAGA (p.Arg379X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4e-06 in 250986 control chromosomes (gnomAD). c.1135_1139delAGAGA has been reported in the literature in individuals affected with Lynch Syndrome and Lynch Syndrome-associated malignancies (e.g. Kets_2006, Shirts_2015, Susswein_2015, Frolova_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17117178, 26681312, 25617771, 26845104). ClinVar contains an entry for this variant (Variation ID: 89174). Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome 1

Pathogenic:1

Aug 01, 2022

Human Genetics Bochum, Ruhr University Bochum

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG criteria used to clasify this variant: PVS1, PM2, PS4 -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg379*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is present in population databases (rs777907133, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with colorectal polyps, endometrial cancer, and cervical cancer (PMID: 17117178, 25617771, 26681312, 26845104, 28514183). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH6 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH6 testing. For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma

Pathogenic:1

May 07, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.9

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

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