2-47798875-C-T

Position:

• chr2-47798875-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_001281493.2(MSH6):​c.-15C>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 0.00000558 in 1,613,908 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MSH6 NM_001281493.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 0.361

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 10 ACMG points.

• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.344
• PP5: Variant 2-47798875-C-T is Pathogenic according to our data. Variant chr2-47798875-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 89574.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47798875-C-T is described in Lovd as [Pathogenic]. Variant chr2-47798875-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.892C>T	p.Arg298*	stop_gained	4/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.892C>T	p.Arg298*	stop_gained	4/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152056 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: 0.00000796 AC: 2 AN: 251272 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135818

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461852 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727226

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152056 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74254

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

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2024	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 Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (PMID: 26552419, 28528517, 29212164, 30256257, 31162827, 30612635, 30877237, 30702970); Not observed at 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: 26552419, 29922827, 28888541, 25637381, 26681312, 28528517, 29212164, 26633542, 30702970, 31162827, 30612635, 30256257, 30063919, 30877237, 31589614, 33087929, 30787465, 31447099) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 23, 2024	PP4, PP5, PM2_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 17, 2019	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient in literature, and found in general population data that is consistent with pathogenicity. -

Lynch syndrome Pathogenic:4

Likely pathogenic, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 19, 2019	The p.Arg298X variant in MSH6 has been reported in at least 2 individuals with MSH6-associated cancers (Goodfellow 2015, Susswein et al. 2016) and has also been identified in 1/15278 African chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 298, which is 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. Moreover, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000108264.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon the predicted impact on the protein and low frequency in controls. ACMG/AMP Criteria applied: PS4_Supporting, PM2, PVS1. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 14, 2016	Variant summary: This c.892C>T variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein. Heterozygous loss-of-function mutations in this gene is an established disease mechanism in Lynch Syndrome (LS) or LS-associated cancers. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg482X, p.Arg911X, p.Arg1035X, etc.). This variant was found in 1/13006 control chromosomes from NHLBI ESP at a frequency of 0.0000769, which is lower than the maximal expected frequency of a pathogenic allele (0.0001421) in this gene. It was not found in approximately 121148 chromosomes from the broad and large populations from ExAC. This variant has been reported in two cases in literature, one known to be diagnosed with Endometrial Cancer with high risk of Lynch Syndrome based on the family history (Goodfellow_2015, Retterer_2015). In addition, the variant has been reported in 10 individuals in UMD database and in two individual by a clinical laboratory (Mayo Clinic Genetic Testing Laboratories) without information about clinical diagnosis. Multiple reputable databases and clinical laboratories have classified this variant as pathogenic. Taken together, this variant has been classified as a Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 29, 2021	The p.R298* pathogenic mutation (also known as c.892C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 892. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been reported in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome, including patients whose tumors demonstrated high microsatellite instability and/or loss of MSH2/MSH6 staining by immunohistochemistry (IHC) (Goodfellow PJ et al. J Clin Oncol, 2015 Dec;33:4301-8; Susswein LR et al. Genet Med, 2016 08;18:823-32; Morak M et al. Fam Cancer, 2017 Oct;16:491-500; Roberts ME et al. Genet Med, 2018 10;20:1167-1174; Long B et al. Gynecol Oncol, 2019 01;152:20-25; Salvador MU et al. J Clin Oncol, 2019 03;37:647-657; Pearlman R et al. J Med Genet, 2019 07;56:462-470; Bennett JA et al. Am J Surg Pathol, 2019 02;43:235-243). 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	Aug 25, 2020	This variant changes 1 nucleotide in exon 4 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-associated cancers (PMID: 26552419, 26681312, 28528517, 29212164). This variant has also been identified in 2/251272 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. -

Lynch syndrome 5 Pathogenic:1

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. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2023

This sequence change creates a premature translational stop signal (p.Arg298*) 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 (rs146816935, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with endometrial cancer (PMID: 26552419). ClinVar contains an entry for this variant (Variation ID: 89574). For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.65	D
Vest4		0.79
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs146816935; hg19: chr2-48026014; COSMIC: COSV99316926; COSMIC: COSV99316926;