2-47800177-C-T

Variant names:

• chr2-47800177-C-T
• rs63751127
• NM_000179.3:c.2194C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000179.3(MSH6):​c.2194C>T​(p.Arg732*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000496 in 1,614,012 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. R732R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MSH6 NM_000179.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: 3.95
• Publications: 22 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-47800177-C-T is Pathogenic according to our data. Variant chr2-47800177-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 89262.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.2194C>T	p.Arg732*	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.2194C>T	p.Arg732*	stop_gained	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152142 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

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250888 AF XY: 0.00

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461870 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000138 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5

Apr 27, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 11, 2022

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; 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: 20028993, 20924129, 15483016, 25525159, 27601186, 26681312, 24728189, 27153395, 28874130, 33087929, 30521064, 30787465, 31851094, 32294063, 31948886, 18301448) -

Nov 08, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

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

- -

Lynch syndrome Pathogenic:4

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 -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Arg732X variant was identified in 2 of 1692 proband chromosomes (frequency: 0.001) from individuals or families with early-onset colorectal cancer or Lynch syndrome (Giráldez 2010, Plaschke 2004). The tumours from the positive probands in these studies showed loss of MSH6 protein by immunohistochemistry; one tumour also showed high microsatellite instability. The variant was also identified in dbSNP (ID: rs63751127) “With Pathogenic allele”, GeneInsight COGR database (classified as pathogenic by a clinical laboratory), HGMD, “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database, UMD (2X as a “causal” variant), and in the ClinVar database (classified as a pathogenic by all three submitters: InSiGHT, Ambry Genetics, and GeneDx). The p.Arg732X variant leads to a premature stop codon at position 732, 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 this 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. -

Sep 13, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg732X variant in MSH6 has been reported in at least 5 individuals with hereditary non-polyposis colorectal cancer (HNPCC) and related tumors (Plaschke 2004 PMID: 15483016, Steinke 2008 PMID: 18301448, Baglietto 2010 PMID: 20028993, Giraldez 2010 PMID: 20924129, Song 2014 PMID: 24728189). This variant has also been identified in 0.001% (1/68036) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This nonsense variant leads to a premature termination codon at position 732, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism for Lynch syndrome. Moreover, this variant was classified as pathogenic on Sept. 05, 2013 by the ClinGen approved InSiGHT expert panel (Variation ID: 89262). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PM2_Supporting, PVS1, 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; PP4_MOD -

Hereditary cancer-predisposing syndrome Pathogenic:2

Dec 02, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R732* pathogenic mutation (also known as c.2194C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2194. This changes the amino acid from an arginine to a stop codon within coding exon 4. This alteration has been reported in multiple individuals satisfying HNPCC/Lynch syndrome clinical criteria with tumors showing microsatellite instability and absence of MSH6 staining on IHC (Plaschke J et al. J. Clin Oncol. 2004;22:4486-4494; Steinke V et al. Eur J Hum Genet. 2008 May;16(5):587-92). This alteration has also been reported in individuals diagnosed with breast, ovarian, pancreatic, prostate and uterine cancers (Song H et al. Hum Mol Genet, 2014 Sep;23:4703-9; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-817; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Roberts ME et al. Genet Med, 2018 10;20:1167-1174; Dondi G et al. Int J Mol Sci, 2020 Sep;21:; Mannucci A et al. Eur J Gastroenterol Hepatol, 2020 03;32:345-349; Wu Y et al. Eur Urol Oncol, 2020 04;3:224-230). 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. -

Mar 28, 2023

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 reported in individuals affected with Lynch syndrome (PMID: 15483016, 18301448, 20028993, 27601186, 28874130) and breast cancer (PMID: 33471991). This variant has been identified in 1/250888 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

Aug 16, 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. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Aug 29, 2022

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.2194C>T (p.Arg732X) 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 and also observed in the HGMD database. The variant allele was found at a frequency of 4e-06 in 250888 control chromosomes. c.2194C>T has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Example: Susswein_2015, Rossi_2017, Baglietto_2010, Song_2014, Jiang_2019 etc.). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

MSH6-related disorder Pathogenic:1

Jun 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 c.2194C>T variant is predicted to result in premature protein termination (p.Arg732*). This variant has been reported in many individuals with Lynch syndrome-associated cancers (Plaschke et al. 2004. PubMed ID: 15483016; Song et al. 2014. PubMed ID: 24728189; Susswein et al. 2016. PubMed ID: 26681312; Jiang et al. 2019. PubMed ID: 30521064; Wu et al. 2020. PubMed ID: 31948886; Pereira et al. 2022. PubMed ID: 35980532). It has also been observed to co-segregate with incomplete penetrance in a family with pancreatic, gastric, or endometrial cancers (Mannucci et al. 2020. PubMed ID: 31851094). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/89262/). Nonsense variants in MSH6 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jan 29, 2025

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.Arg732*) 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 (rs63751127, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer and Lynch syndrome (PMID: 15483016, 18301448, 20028993, 24728189). 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: 89262). For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma Pathogenic:1

Mar 09, 2024

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	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		4.0
Vest4		0.92
GERP RS		5.5
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: rs63751127; hg19: chr2-48027316; COSMIC: COSV52279460; COSMIC: COSV52279460;