rs267608077

Positions:

• chr2-47799111-AAAGAG-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000179.3(MSH6):​c.1135_1139del​(p.Arg379Ter) 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 (★★★). 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
• Clinical Significance: Pathogenic reviewed by expert panel P:18 U:1
• Conservation: PhyloP100: 5.86

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 89174.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47799111-AAAGAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.1135_1139del	p.Arg379Ter	frameshift_variant	4/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.1135_1139del	p.Arg379Ter	frameshift_variant	4/10	1	NM_000179.3	ENSP00000234420	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250986 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135632

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 SAS 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: 4 AN: 1461882 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:6 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2023	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) -
Likely pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 25, 2019	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. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Lynch syndrome 5 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 11, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 19, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Aug 01, 2022	ACMG criteria used to clasify this variant: PVS1, PM2 -

Lynch syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Sep 22, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation resulting in a stop codon -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2022	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 (PMID: 17117178), endometrial and/or ovarian cancer (PMID: 17453009, 26845104, 25617771), and cervical cancer (PMID: 26681312). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 07, 2022	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. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 21, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Human Genetics Bochum, Ruhr University Bochum

Aug 01, 2022

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

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2023

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). ClinVar contains an entry for this variant (Variation ID: 89174). For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267608077; hg19: chr2-48026250;