2-47800211-T-TG

Position:

• chr2-47800211-T-TG

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.2230dup​(p.Glu744GlyfsTer12) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000248 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 4.01

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 2-47800211-T-TG is Pathogenic according to our data. Variant chr2-47800211-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.2230dup	p.Glu744GlyfsTer12	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.2230dup	p.Glu744GlyfsTer12	frameshift_variant	4/10	1	NM_000179.3	ENSP00000234420	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250900 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135598

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461880 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2024	Observed in individuals with MSH6-related cancers (PMID: 23733757, 30067863, 30093976, 28888541, 36744932); Frameshift 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23733757, 30067863, 30093976, 28944238, 32719484, 30787465, 29922827, 28888541, 28514183, 36744932) -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 15, 2023	The MSH6 c.2230dup; p.Glu744GlyfsTer12 variant (rs786201050) is reported in the literature in several individuals affected with Lynch syndrome-associated cancers (Brand 2018, Chan 2018, DeRycke 2017, Espenschied 2017, Lilyquist 2017, Ward 2013). This variant is reported in ClinVar (Variation ID: 183739) and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be likely pathogenic. References: Brand R et al. Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma. Cancer. 2018 Sep 1;124(17):3520-3527. PMID: 30067863. Chan GHJ et al. Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers. Oncotarget. 2018 Jul 17;9(55):30649-30660. PMID: 30093976. DeRycke MS et al. Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. Mol Genet Genomic Med. 2017 Jul 23;5(5):553-569. PMID: 28944238. Espenschied CR et al. Multigene Panel Testing Provides a New Perspective on Lynch Syndrome. J Clin Oncol. 2017 Aug 1;35(22):2568-2575. PMID: 28514183. Lilyquist J et al. Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol. 2017 Nov;147(2):375-380. PMID: 28888541. Ward RL et al. Population-based molecular screening for Lynch syndrome: implications for personalized medicine. J Clin Oncol. 2013 Jul 10;31(20):2554-62. PMID: 23733757. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 09, 2023	PP5, PM2, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 24, 2019	This frameshift variant causes the premature termination of MSH6 protein synthesis. In addition, this variant has been reported in the literature in individuals with personal and family history of colorectal cancer (PMID: 28944238 (2017), 23733757 (2013)). Based on the available information, this variant is classified as pathogenic. -

Lynch syndrome 5 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 16, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 04, 2018	The MSH6 c.2230dupG (p.Glu744GlyfsTer12) variant, also reported as c.2228_2229insG, results in a frameshift, and is predicted to result in premature termination of the protein. The p.Glu744GlyfsTer12 variant has been reported in two studies and is found in a compound heterozygous state in two probands with colorectal cancer (Ward et al. 2013; DeRycke et al. 2017). The variant is reported at a frequency of 0.000016 in the European (non-Finnish) population from the Genome Aggregation Database but this is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of frameshift variants and evidence from literature, the p.Glu744GlyfsTer12 variant is classified as likely pathogenic for Lynch syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 25, 2021	The c.2230dupG pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of G at nucleotide position 2230, causing a translational frameshift with a predicted alternate stop codon (p.E744Gfs*12). This mutation has been reported in multiple Lynch syndrome individuals (Ward RL et al. J. Clin. Oncol. 2013 Jul;31:2554-62; Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Brand R et al. Cancer, 2018 09;124:3520-352; Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 07, 2023	This variant inserts 1 nucleotide 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 reported in individuals affected with ovarian and endometrial cancer (PMID: 30093976), colorectal cancer (PMID: 23733757, 28944238), pancreatic adenocarcinoma (PMID: 30067863 ), and breast cancer (PMID: 29345684). This variant has been identified in 2/282300 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and has been reported in a control sample (PMID: 30128536). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Endometrial carcinoma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 09, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH6 p.Glu744Glyfs*12 variant was identified in 2 of 2872 proband chromosomes (frequency: 0.0007) from individuals or families with endometrial, ovarian, or colorectal cancer (Chan 2018, Ward 2013). The variant was also identified in dbSNP (ID: rs786201050) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics and three other submitters), and UMD-LSDB (1x as causal). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). This variant was identified by our laboratory in a patient with MSH6-deficient endometrial cancer. The c.2230dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 744 and leads to a premature stop codon at position 755. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 10, 2023

Variant summary: MSH6 c.2230dupG (p.Glu744GlyfsX12) 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 250900 control chromosomes (gnomAD). c.2230dupG has been reported in the literature in individuals affected with colorectal cancer or ovarian and endometrial cancer with family histories of cancer (e.g. Ward_2013, Chan_2018). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23733757, 30093976). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

MSH6-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

The MSH6 c.2230dupG variant is predicted to result in a frameshift and premature protein termination (p.Glu744Glyfs*12). This variant has been reported in individuals with colorectal cancer, pancreatic ductal adenocarcinoma, and endometrium ovarian cancer (Ward et al 2013. PubMed ID: 23733757; Brand et al. 2018. PubMed ID: 30067863; Table 4, Chan et al. 2018. PubMed ID: 30093976). This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant is interpreted as likely pathogenic/pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/183739). Frameshift variants in MSH6 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Lynch syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 18, 2023

This variant inserts 1 nucleotide 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ovarian and endometrial cancer (PMID: 30093976), colorectal cancer (PMID: 23733757, 28944238), and breast cancer (PMID: 29345684). This variant has been identified in 2/282300 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and has been reported in a control sample (PMID: 30128536). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

This sequence change creates a premature translational stop signal (p.Glu744Glyfs*12) 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 (rs773290953, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 23733757). ClinVar contains an entry for this variant (Variation ID: 183739). For these reasons, this variant has been classified as Pathogenic. -

Lynch syndrome 5;C5399763:Mismatch repair cancer syndrome 1 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 03-24-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs786201050; hg19: chr2-48027350;