2-47800714-C-T

Position:

chr2-47800714-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000179.3(MSH6):c.2731C>T(p.Arg911*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,924 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 (★★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MSH6
NM_000179.3 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:27

Conservation

PhyloP100: 2.62

Variant links:

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]

MSH6 links:

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 links:

MSH6 (HGNC:):

MSH6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 2-47800714-C-T is Pathogenic according to our data. Variant chr2-47800714-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 89312.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800714-C-T is described in Lovd as [Pathogenic]. Variant chr2-47800714-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 linkuse as main transcript	c.2731C>T	p.Arg911*	stop_gained	4/10	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 linkuse as main transcript	c.2731C>T	p.Arg911*	stop_gained	4/10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74274

show subpopulations

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000481

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 29, 2024	PP4, PM2, PS4_moderate, PVS1 -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2022	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: 24244552, 25117503, 29978187, 25525159, 23263490, 12732731, 15483016, 25637381, 15098177, 20487569, 23047549, 28176205, 26681312, 28873162, 20028993, 25559809, 16885385, 29212164, 15236168, 29760388, 29750335, 30521064, 31857677, 32242007, 31447099, 32081490, 31589614, 32719484, 30787465, 33087929, 34178123, 29130549) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 06, 2020	This nonsense variant is predicted to cause the premature termination of MSH6 protein synthesis. In the published literature, the variant has been reported in multiple individuals suspected of having Lynch syndrome in the published literature (PMIDs: 15236168 (2004), 23263490 (2013), 25117503 (2014), 26681312 (2015), 28176205 (2017), 29212164 (2017), 29978187 (2018), 30521064 (2019), 31857677 (2020), 32242007 (2020)). Based on the available information, this variant is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2017	The MSH6 c.2731C>T; p.Arg911Ter variant (rs63751017) has previously been described in individuals and families with Lynch syndrome (Goodfellow 2003, Pal 2012, Plaschke 2004, Rosty 2014, Talseth-Palmer 2010). It is reported in the ClinVar database as pathogenic (Variation ID: 89312), and observed in the general population at a very low allele frequency of 0.008 percent (1/13006 alleles) in the Exome Variant Server, and 0.003 percent (1/30970 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript. Based on the above information, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Arg911Ter: https://www.ncbi.nlm.nih.gov/clinvar/variation/89312/ Goodfellow PJ et al. Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proc Natl Acad Sci U S A. 2003 May 13;100(10):5908-13. Pal T et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. 2012 Nov 6;107(10):1783-90. Plaschke J et al. Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. J Clin Oncol. 2004 Nov 15;22(22):4486-94. Rosty C et al. High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry. Fam Cancer. 2014 Dec;13(4):573-82. Talseth-Palmer BA et al. MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. Hered Cancer Clin Pract. 2010 May 21;8(1):5. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	MSH6: PVS1, PM2, PS4:Moderate -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 07, 2022	- -

Lynch syndrome 5

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 06, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Nov 26, 2017	The c.2731C>T (p.Arg911) variant in the MSH6 gene is predicted to introduce a premature translation stop codon. This variant has been reported in the literature in multiple individuals with ovarian, colorectal, or prostate cancer (PMID: 12732731, 23047549, 23263490, 15236168, 15483016, 25117503, 16885385). The c.2731C>T (p.Arg911) variant in the MSH6 gene is classified as pathogenic. -
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	Myriad Genetics, Inc.	Mar 29, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2019	The p.Arg911X variant in MSH6 has been reported in at least 13 individual with MSH6-associated cancers and segregated in at least 4 affected relatives (Goodfellow 2003, Buttin 2004, Hendriks 2004, Plaschke 2004, Hampel 2006, Talseth-Palmer 2010, Pal 2012, Palles 2013, Rosty 2014, Susswein 2015, Akbari 2017, Raskin 2017). This variant has also been reported in ClinVar (Variation ID 89312) and has been identified in 1/15426 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 911, 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 Lynch syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1; PS4; PP1; PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 31, 2024	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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with colorectal, ovarian, endometrial, small bowel and prostate cancer (PMID: 12732731, 15483016, 16885385, 19723918, 20587412, 25117503, 25559809, 26681312, 28176205, 29212164, 32081490, 32941469), in families affected with Lynch syndrome (PMID: 15236168, 20028993, 20487569, 23263490), and an individual affected with uveal melanoma (PMID: 32081490). This variant has been identified in 1/31398 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 cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 18, 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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with colorectal, ovarian, endometrial, small bowel and prostate cancer (PMID: 12732731, 15483016, 16885385, 19723918, 20587412, 25117503, 25559809, 26681312, 28176205, 29212164, 32081490, 32941469), in families affected with Lynch syndrome (PMID: 15236168, 20028993, 20487569, 23263490), and an individual affected with uveal melanoma (PMID: 32081490). This variant has been identified in 1/31398 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	curation	Sema4, Sema4	Dec 08, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 14, 2022	The p.R911* pathogenic mutation (also known as c.2731C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2731. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been reported in multiple individuals and families diagnosed with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Goodfellow PJ et al. Proc. Natl. Acad. Sci. USA. 2003 May;100:5908-13; Hendriks YM et al. Gastroenterology. 2004 Jul;127:17-25; Plaschke J et al. J. Clin. Oncol. 2004 Nov;22:4486-94; Hampel H et al. Cancer Res. 2006 Aug;66:7810-7; Baglietto L et al. J. Natl. Cancer Inst. 2010 Feb;102:193-201; Palles C et al. Nat. Genet. 2013 Feb;45:136-44; Chubb D et al. J. Clin. Oncol. 2015 Feb;33:426-32; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Raskin L et al. Oncotarget. 2017 Nov;8:93450-93463). 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. -

Endometrial carcinoma

Pathogenic:2

Pathogenic, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 05, 2024	- -

Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 10, 2021

- -

Carcinoma of colon

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MSH6 p.Arg311* variant has been previously reported in the literature in at least 5 of 2738 proband chromosomes in individuals with Lynch syndrome related tumours and microsatellite instability (Selected publications: Plaschke 2004, Hendriks 2004, Hampel 2006, Goodfellow 2003). The p.Arg311* variant is predicted to cause a premature stop codon at position 311, which is then 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 for Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant is 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

Jun 08, 2022

Variant summary: MSH6 c.2731C>T (p.Arg911X) 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 was absent in 250878 control chromosomes. c.2731C>T has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer and endometrial cancer (e.g. Goodfellow_2003, Hendricks_2004, Plasche_2004, Hampel_2006, Talseth-Palmer_2010). These data indicate that the variant is very likely to be associated with disease. Thirteen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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 16, 2024

This sequence change creates a premature translational stop signal (p.Arg911*) 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 (rs63751017, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 12732731, 15483016, 20487569, 23047549, 23263490). ClinVar contains an entry for this variant (Variation ID: 89312). For these reasons, this variant has been classified as Pathogenic. -

Breast carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.95

Vest4

0.92

GERP RS

2.8

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over