2-47800996-C-T

Variant names:

• chr2-47800996-C-T
• rs63750563
• NM_000179.3:c.3013C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000179.3(MSH6):​c.3013C>T​(p.Arg1005*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,409,816 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. R1005R) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MSH6 NM_000179.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:22
• Conservation: PhyloP100: 3.23
• Publications: 26 publications found

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]

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

ACMG classification

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 2-47800996-C-T is Pathogenic according to our data. Variant chr2-47800996-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 89330.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	c.3013C>T	p.Arg1005*	stop_gained	Exon 4 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3013C>T	p.Arg1005*	stop_gained	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000478 AC: 1 AN: 209220 AF XY: 0.00000898

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: 0.0000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1409816 Hom.: 0 Cov.: 34 AF XY: 0.00000287 AC XY: 2 AN XY: 695910

African (AFR) AF: 0.00 AC: 0 AN: 31562

American (AMR) AF: 0.00 AC: 0 AN: 36574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22688

East Asian (EAS) AF: 0.00 AC: 0 AN: 39296

South Asian (SAS) AF: 0.00 AC: 0 AN: 76352

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5492

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1088366

Other (OTH) AF: 0.00 AC: 0 AN: 58024

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000465 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:8

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSH6: PVS1, PM2, PS4:Moderate -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 02, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2014

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2024

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 the heterozygous state in individuals with Lynch syndrome (PMID: 15483016, 21247423, 27928858); Observed with a pathogenic MSH6 variant in an individual with constitutional mismatch repair-deficiency (CMMR-D) (PMID: 29130549); 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: 21247423, 23544471, 37937776, 29130549, 29922827, 25525159, 15483016, 26203307, 26552419, 24278394, 27928858, 28944238, 33087929, 1958182, 32660107, 30572730, 32719484, 29625052, 36451132) -

May 08, 2015

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome 5 Pathogenic:5

Aug 21, 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. -

Jul 21, 2023

deCODE genetics, Amgen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The variant NM_000179.3:c.3013C>T (chr2:47800996) in MSH6 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic. -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The stop gained variant c.3013C>T(p.Arg1005Ter) in MSH6 gene has been reported in heterozygous state in mutliple individuals with hereditary non-polyposis colon cancer (HNPCC)/Lynch syndrome (Adachi M, et al., 2017). The variant has 0.0005% allele frequency in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Thompson BA, et al., 2014). For these reasons, this variant has been classified as Pathogenic. -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Pathogenic:4

Jan 04, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is predicted to result in loss of protein function through nonsense-mediated or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with MSH6-related cancer and in at least one individual with constitutional mismatch repair deficiency and a second MSH6 loss-of-function variant (PMID: 29130549, 27928858, 21247423). This variant is rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -

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 -

Oct 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg1005X variant in MSH6 has been previously reported in 5 individuals with colorectal cancer, 1 individual with endometrial cancer, 1 individual with multiple colorectal adenomas, and 2 individuals with Lynch syndrome, and segregated with disease in 2 affected relatives from 1 family (Colley 2005, Castillejo 2011, Plaschke 2004, De Lellis2013, Goodfellows 2015, Adachi 2017, Pan 2019, Keranen 2018, Tanskanen 2013). It has also been identified in 1/99286 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89330). This nonsense variant leads to a premature termination codon at position 1005, 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 individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2, PS4_Moderate. -

Feb 04, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1; PM2_SUP; PM3_SUP -

Hereditary cancer-predisposing syndrome Pathogenic:2

Nov 15, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1005* pathogenic mutation (also known as c.3013C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 3013. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been identified in multiple individuals diagnosed with hereditary non-polyposis colon cancer (HNPCC)/Lynch syndrome (Plaschke, J et al. J Clin Oncol. 2004 Nov 15;22(22):4486-94; Castillejo, A et al. BMC Med Genet. 2011 Jan 19;12:12; Adachi M et al. Obstet. Gynaecol. Res. 2017 Feb;43(2):416-420; De Lellis L et al. PLoS One, 2013 Nov;8:e81194; Keränen A et al. Scand J Gastroenterol, 2018 Dec;53:1535-1540; Olkinuora A et al. Cancers (Basel), 2020 Jul;12; Ambry internal data). This mutation has also been reported in an individual with constitutional mismatch repair deficiency (CMMRD) (Guerrini-Rousseau L et al. Neurooncol Adv Dec;1:vdz033). Of note, this alteration is also designated as p.R1005X in published literature. 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. -

Jan 15, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 identified in 1/209220 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. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Oct 15, 2020

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.3013C>T (p.Arg1005X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.8e-06 in 209220 control chromosomes (gnomAD). c.3013C>T has been reported in the literature in multiple individuals affected with colorectal cancer and Lynch syndrome (Plaschke_2004, Castillejo_2011, DeLellis_2013, Adachi_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Oct 29, 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.Arg1005*) 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 (rs63750563, gnomAD 0.001%). This premature translational stop signal has been observed in individual(s) with colorectal cancer, endometrial cancer and suspected of having Lynch syndrome (PMID: 15483016, 21247423, 23544471, 26552419, 27928858, 28944238). 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. ClinVar contains an entry for this variant (Variation ID: 89330). For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma Pathogenic:1

Jun 30, 2021

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
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		3.2
Vest4		0.90
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs63750563; hg19: chr2-48028135; COSMIC: COSV99315067; COSMIC: COSV99315067;