2-47803449-C-T

Position:

• chr2-47803449-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_001406831.1(MSH6):​c.-18C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: MSH6 NM_001406831.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic reviewed by expert panel P:32
• Conservation: PhyloP100: 3.28

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]

MSH6 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.528
• PP5: Variant 2-47803449-C-T is Pathogenic according to our data. Variant chr2-47803449-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 89352.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47803449-C-T is described in Lovd as [Pathogenic]. Variant chr2-47803449-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3202C>T	p.Arg1068*	stop_gained	5/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3202C>T	p.Arg1068*	stop_gained	5/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461876 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000719

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74284

Gnomad4 AFR AF: 0.0000483

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

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:32

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Mar 27, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2024	Observed in individuals with personal and/or family history consistent with pathogenic variants in this gene (PMID: 11807791, 18301448, 20028993, 20379851, 20487569, 23403630, 26552419, 28528517, 30702970, 34178123); 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; 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, 24323032, 20487569, 11807791, 18301448, 25741868, 25525159, 21247423, 20028993, 28152038, 26552419, 23403630, 15483016, 28002797, 20379851, 28528517, 29360161, 29489754, 30702970, 30324682, 30322717, 34178123, 34426522, 30787465, 33804961, 34887416, 36243179, 35798629, Tsukanov2023[CaseReport], 31447099, 37453313, 34326862, 35089076, 36988593, 31742824) -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 21, 2023	This nonsense variant causes the premature termination of MSH6 protein synthesis. The frequency of this variant in the general population, 0.00002 (3/152096 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals/families with Lynch syndrome- associated cancers (PMIDs: 11807791 (2002), 18301448 (2008), 24323032 (2014), 28528517(2017), 29360161 (2018), 30324682 (2018), 30702970 (2019), 33422027 (2021), and 34178123 (2021)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Jun 17, 2022	PS4_MOD, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MSH6: PVS1, PM2, PS4:Moderate -

Lynch syndrome 5 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 22, 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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 03, 2023	Criteria applied: PVS1,PS4,PM2_SUP,PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jan 30, 2018	This c.3202C>T variant in the MSH6 gene has been reported in multiple rectal cancer, HNPCC and Lynch syndrome patients [PMID:18301448, 20028993, 24323032] while not observed in general population according to gnomad database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on the current evidence, this c.3202C>T (p.Arg1068*) in the MSH6 gene is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jul 03, 2020	This nonsense variant found in exon 5 of 10 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been reported in multiple individuals and families with Lynch syndrome-associated cancers such as colorectal cancer, endometrial cancer, pancreatic cancer and renal cancer (PMID: 11807791, 24323032, 20379851, 18301448, 20028993). This variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.3202C>T (p.Arg1068Ter) variant is classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 09, 2024	The p.R1068* pathogenic mutation (also known as c.3202C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at nucleotide position 3202. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been reported in multiple hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome families, several with tumors showing high microsatellite instability and/or absent MSH6 protein expression on IHC (Plaschke J et al. Int. J. Cancer, 2002 Feb;97:643-8; Steinke V et al. Eur J Hum Genet, 2008 May;16:587-92; Baglietto L et al. J Natl Cancer Inst, 2010 Feb;102:193-201; Talseth-Palmer BA et al. Hered Cancer Clin Pract, 2010 May;8:5; McIlvried DE et al. Fam. Cancer, 2010 Sep;9:377-81; Thodi G et al. BMC Cancer, 2010 Oct;10:544; Ward RL et al. J Clin Oncol, 2013 Jul;31:2554-62; Buchanan DD et al. J Clin Oncol, 2014 Jan;32:90-100; Goodfellow PJ et al. J Clin Oncol, 2015 Dec;33:4301-8; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Iordache PD et al. J Cell Mol Med, 2018 12;22:6068-6076; Dudley B et al. Cancer, 2018 04;124:1691-1700; Salvador MU et al. J Clin Oncol, 2019 03;37:647-657; Xu Y et al. BMC Cancer, 2021 Jan;21:45). 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	Dec 21, 2022	This variant changes 1 nucleotide in exon 5 of the MSH6 gene, creating a 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 Lynch syndrome or Lynch syndrome associated cancers (PMID: 11807791, 18301448, 20028993, 20379851, 20487569, 20937110, 24323032, 29967336). This variant has not been identified 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	Vantari Genetics	Oct 28, 2015	- -

Lynch syndrome Pathogenic:2

Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation resulting in a stop codon -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 13, 2024	The c.3202C>T (p.Arg1068*) variant in the MSH6 gene is located on the exon 5 and introduces a premature translation termination codon (p.Arg1068*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with Lynch syndrome-associated cancers (PMID: 30324682, 29360161, 33422027, 28528517, 20487569). Loss-of-function variants of MSH6 are known to be pathogenic, and frameshift/truncating variants located upstream and downstream to this position have been reported in individuals with Lynch syndrome-associated cancers (PMID: 30376427, 18269114, 29345684). The variant is reported in ClinVar as pathogenic (ID: 89352) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.3202C>T (p.Arg1068*) variant of MSH6 has been classified as pathogenic. -

Endometrial carcinoma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 18, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 23, 2019	- -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH6 p.Arg1068X variant was identified in 8 of 3948 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome and endometrial cancer, and is classified as pathogenic in the literature (Buchanan 2014, Plaschke 2002, Plaschke 2004, Steinke 2008, Talseth Palmer 2010, Ward 2013, Castillejo 2011, Mcllvried 2010). The variant was also identified in the following databases: dbSNP (ID: rs63749843) as “With Pathogenic allele”, ClinVar (10x as pathogenic, reviewed by an expert panel), Clinvitae (4x as pathogenic), COGR, Cosmic (4x in colon cancer), UMD-LSDB (12x as "causal"), Insight Colon Cancer Gene Variant Database (15 x as pathogenic), and Mismatch Repair Genes Variant Database. The variant was not identified in MutDB, Zhejiang Colon Cancer Database, or Insight Hereditary Tumors Database. The variant was also identified by our laboratory in 2 individuals with uterine and endometrial cancer. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Arg1068X variant leads to a premature stop codon at position 1068, which is predicted to lead to 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

Oct 10, 2023

Variant summary: MSH6 c.3202C>T (p.Arg1068X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251326 control chromosomes. c.3202C>T has been reported in the literature in multiple individuals affected with Lynch Syndrome (Baglietto_2010, Dudley_2018, Plaschke_2002, Steinke_2008, Talseth-Palmer_2010, Thodi_2010). 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: 20028993, 29360161, 11807791, 18301448, 20487569, 20937110, 24362816, 25525159). 19 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Pathway Genomics

Oct 30, 2014

- -

Lynch-like syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Constitutional Genetics Lab, Leon Berard Cancer Center

Jul 01, 2019

- -

Endometrial carcinoma;C1833477:Lynch syndrome 5;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

This sequence change creates a premature translational stop signal (p.Arg1068*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer, endometrial cancer, pancreatic cancer, and renal cancer (PMID: 11807791, 18301448, 20028993, 20379851, 24323032). ClinVar contains an entry for this variant (Variation ID: 89352). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
Vest4		0.95
GERP RS		2.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs63749843; hg19: chr2-48030588; COSMIC: COSV52273620; COSMIC: COSV52273620;