2-47799427-C-T

Position:

• chr2-47799427-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000179.3(MSH6):​c.1444C>T​(p.Arg482*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000558 in 1,613,850 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. R482R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MSH6 NM_000179.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:19
• Conservation: PhyloP100: 3.90

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-47799427-C-T is Pathogenic according to our data. Variant chr2-47799427-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 89194.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47799427-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.1444C>T	p.Arg482*	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.1444C>T	p.Arg482*	stop_gained	4/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151978 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: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461872 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727234

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: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151978 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74230

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	MSH6: PVS1, PP1, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2021	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 (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in multiple individuals with Lynch syndrome-associated cancers, including colon cancers which demonstrate absence of MSH6 protein by immunohistochemistry (Hendriks 2004, Nilbert 2009, Baglietto 2010, Sjursen 2010, Klarskov 2011, Okkels 2012, Therkildsen 2015, Yurgelun 2015, Young 2018); This variant is associated with the following publications: (PMID: 28460341, 15236168, 20587412, 18566915, 25648859, 25980754, 22495361, 25525159, 20028993, 19575290, 18415027, 26517685, 27013479, 21836479, 29945567, 32710294, 31297992, 30291343, 32832836, 32794656) -

Lynch syndrome 5 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 30, 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	Institute of Human Genetics, University of Leipzig Medical Center	May 24, 2023	Criteria applied: PVS1,PS4_MOD,PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 09, 2016	- -

Lynch syndrome Pathogenic:3

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 02, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 18, 2024	The c.1444C>T variant in the MSH6 gene is located on the exon 4 and introduces a premature translation termination codon (p.Arg482*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with Lynch syndrome-associated cancer (PMID: 22495361, 26517685, 27601186, 20587412, 26437257). Loss-of-function variants of MSH6 are known to be pathogenic (PMID: 30376427, 18269114, 29345684). Other loss-of-function variants located in the same exon (p.Tyr433*, p.Tyr524*) have been interpreted as pathogenic by the expert panel (ClinVar ID: 89185, 89202). This variant has been reported as pathogenic by the expert review panel in ClinVar (ID: 89194). This variant is rare (9/1613850 chromosomes) in general population according to gnomAD. Therefore, the c.1444C>T (p.Arg482*) variant in the MSH6 gene has been classified as pathogenic. -

Endometrial carcinoma Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 05, 2022	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated -
Pathogenic, no assertion criteria provided	clinical testing	CZECANCA consortium	Feb 21, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 19, 2023	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: 15236168, 19575290, 20587412, 22495361, 28460341) and colorectal cancer (PMID: 20028993). This variant has been identified in 1/31384 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 28, 2022	The p.R482* pathogenic mutation (also known as c.1444C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1444. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation was detected in a family that met Amsterdam II criteria and the mutation showed moderate segregation with disease (Hendriks YM et al. Gastroenterology 2004 Jul;127(1):17-25). The mutation has also been reported in multiple patients with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome, some of whom have been shown to have tumors with loss of MSH6 protein on immunohistochemistry (IHC) (Nilbert M et al. Fam. Cancer 2009 Jun;8(1):75-83; Jensen UB et al. Breast Cancer Res. Treat. 2010 Apr;120:777-82; Okkels H et al. Appl. Immunohistochem. Mol. Morphol. 2012 Oct;20:470-7). The p.R482* mutation was identified in a 34 year-old woman with choroid plexus carcinoma (CPC) that demonstrated absence of MSH6 protein by IHC (Zhu VW et al. Clin Neurol Neurosurg 2017 Jul;158:46-48). 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. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH6 p.Arg482X variant was identified in 6 of 3135 proband chromosomes (frequency: 0.002) from individuals or families with CRC and prostate cancer (Hendriks 2004, Nilbert 2008, Dominguez-Valentin 2016). The variant was also identified in dbSNP (ID: rs63750909) as “With Pathogenic allele” ,ClinVar (5x, as pathogenic, by InSight, Invitae, GeneDx, Counsyl, Ambry Genetics), Clinvitae (3x, as pathogenic, by ClinVar and Clinvitae), Cosmic (as pathogenic), UMD-LSDB (8 records, as causal), Insight Colon Cancer Gene Variant Database (4x, as class 5, pathogenic), Mismatch Repair Genes Variant Database (2x as pathogenic), Insight Hereditary Tumors Database (5x , as class 5, "affects function”). The variant was not identified in MutDB, GeneInsight-COGR, Zhejiang Colon Cancer databases. The variant was identified in control databases in 1 of 30956 chromosomes at a frequency of 0.000032 in East Asian population (Genome Aggregation Consortium Feb 27, 2017). The p.Arg482X variant leads to a premature stop codon at position 482, which is predicted to lead to a truncated or absent protein and loss of function.4. Loss of function variants of the MSH6 gene are an established mechanism of disease in colorectal cancer 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 colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 23, 2023

This sequence change creates a premature translational stop signal (p.Arg482*) 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 (rs63750909, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 15236168, 20028993, 20587412, 21836479, 22495361). ClinVar contains an entry for this variant (Variation ID: 89194). For these reasons, this variant has been classified as Pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

Mar 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.87
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs63750909; hg19: chr2-48026566; COSMIC: COSV52288483; COSMIC: COSV52288483;