2-47806641-C-T

Position:

chr2-47806641-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The ENST00000234420.11(MSH6):c.3991C>T(p.Arg1331Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,608,208 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. R1331R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MSH6
ENST00000234420.11 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:25

Conservation

PhyloP100: 0.803

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-47806641-C-T is Pathogenic according to our data. Variant chr2-47806641-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 42472.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47806641-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3 linkuse as main transcript	c.3991C>T	p.Arg1331Ter	stop_gained	9/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 linkuse as main transcript	c.3991C>T	p.Arg1331Ter	stop_gained	9/10	1	NM_000179.3	ENSP00000234420	P4	P52701-1

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150928

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000407

AC:

AN:

245746

Hom.:

AF XY:

0.00000751

AC XY:

AN XY:

133194

show subpopulations

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 SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1457280

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725140

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:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000663

AC:

AN:

150928

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73588

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Lynch syndrome 5

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 02, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 08, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Sep 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	May 31, 2023	ACMG criteria used to clasify this variant:PVS1, PS4_MOD, PM1, PS3_SUP, PM2_SUP -
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. Functional studies indicate this variant impacts protein function [PMID:16418736]. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 14, 2018	The c.3991C>T (p.Arg1331) variant in the MSH6 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated individuals with Lynch Syndrome-associated tumors and loss of MSH6 expression through immunohistochemistry staining were identified in the tumors of these individuals (PMID 16034045,18301448, 20587412). This variant has also been reported in two individuals with constitutional mismatch repair syndrome. One the two individuals carry this variant in trans with a likely pathogenic MSH6 variant (p.Arg1076Cys, PMID 16418736) and the other individual was homozygous with this variant (PMID 26318770). This variant is extremely rare in general population databases. Therefore, this c.3991C>T (p.Arg1331) variant in the MSH6 gene is classified as pathogenic. -

not provided

Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 06, 2022	This nonsense variant causes the premature termination of MSH6 protein synthesis. A published experimental study indicated that this variant results in partial skipping of exon 9 (PMID: 16418736). Additionally, this variant has been reported in individuals with breast (PMID: 26681312 (2016)), ovarian (PMID: 30322717 (2018)), endometrial (PMIDs: 16034045 (2005) and 26552419 (2015)), colorectal (PMIDs: 20587412 (2010), 21056691 (2011), 22081473 (2012), 26318770 (2015), and 27601186 (2016)), and other lynch-related cancers whose tumors showed loss of MSH6 expression in the immunohistochemistry staining (PMIDs: 16034045 (2005), 18301448 (2008), 20587412 (2010), and 22081473 (2012)). In addition, this variant has also been reported in a couple of individuals with constitutional mismatch repair syndrome in the compound heterozygous state with another pathogenic MSH6 variant or in the homozygous state (PMIDs: 16418736 (2006) and 26318770 (2015)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2024	Observed in the homozygous or compound heterozygous state in individuals with a personal history consistent with constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 16418736, 26318770); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 30 amino acids are lost, and also demonstrated to result in partial skipping of exon 9 (PMID: 16418736); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24989436, 25525159, 18409202, 18709565, 26681312, 26552419, 26318770, 12019211, 22081473, 16034045, 21056691, 21674763, 21376568, 18301448, 21642682, 16418736, 27601186, 24362816, 19851887, 30322717, 31447099, 32019277, 21120944, 17531815, 33087929, 34445333, 32427313, 30787465, 28888541, 29922827, 36744932, 29345684, 20587412, 27380347, 31054147, 33471991) -
Likely pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Jun 20, 2023	- -

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 (variant causes splicing aberration) -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	The c.3991C>T (p.Arg1331) variant in the MSH6 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated individuals with Lynch Syndrome-associated tumors and loss of MSH6 expression through immunohistochemistry staining were identified in the tumors of these individuals (PMID 16034045,18301448, 20587412). This variant has also been reported in two individuals with constitutional mismatch repair syndrome. One the two individuals carry this variant in trans with a likely pathogenic MSH6 variant (p.Arg1076Cys, PMID 16418736) and the other individual was homozygous with this variant (PMID 26318770). This variant is extremely rare in general population databases. Therefore, this c.3991C>T (p.Arg1331) variant in the MSH6 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 27, 2021	The p.Arg1331X variant in MSH6 has been reported in the heterozygous state in 6 individuals with MSH6-associated cancers, some of whose tumors demonstrated loss of MSH6 expression on immunohistochemistry (IHC) analysis (Stormorken 2005 PMID:16034045, Sjursen 2010 PMID:20587412, Bonadona 2011 PMID:21642682, Susswein 2015 PMID:26681312, LMM data). This variant has also been reported in 2 individuals with clinical features of constitutional mismatch repair syndrome in the compound heterozygous state with another MSH6 variant (Plaschke 2006 PMID:16418736) or in the homozygous state (Lavoine 2015 PMID:26318770). In addition, the p.Arg1331X variant has been identified in 0.001% (1/67908) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1331. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. This has been corroborated by studies have demonstrated that the variant results in skipping of exon 9, giving rise to a truncated mRNA leading to drastically reduced MSH6 protein levels, suggesting that this truncated protein is unstable (Plaschke 2006 PMID:16418736). Moreover, the p.Arg1331X variant has been classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV000108181.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PVS1_Strong, PM3, PS3_Moderate. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 27, 2024	The p.R1331* pathogenic mutation (also known as c.3991C>T), located in coding exon 9 of the MSH6 gene, results from a C to T substitution at nucleotide position 3991. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been reported in multiple individuals with Lynch syndrome (Plaschke J et al. Eur. J. Hum. Genet. 2006 May;14:561-6; Sjursen W et al. J. Med. Genet. 2010 Sep;47:579-85; van Lier MG et al. J. Pathol. 2012 Apr;226:764-74; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835), including at least one with breast cancer (Roberts ME et al. Genet. Med. 2018 10;20:1167-1174) and one individual with ovarian cancer (Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488). This mutation has also been reported in the homozygous state in an individual with constitutional mismatch repair deficiency who was diagnosed with multiple café-au-lait macules and colorectal cancer at age 11 (Lavoine N et al. Med. Genet. 2015 Nov;52:770-8). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 21, 2023	This variant changes 1 nucleotide in exon 9 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 colorectal and/or endometrial cancer, Lynch syndrome, and Constitutional mismatch repair-deficiency syndrome (PMID: 16034045, 16418736, 20587412, 21056691, 21674763, 22081473, 26318770, 26552419, 27601186, 29345684). This variant has been identified in 1/245746 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. -

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

Mar 17, 2022

- -

Breast and/or ovarian cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 06, 2023

- -

Hereditary nonpolyposis colon cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 26, 2022

Variant summary: MSH6 c.3991C>T (p.Arg1331X) 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. The variant allele was found at a frequency of 4.1e-06 in 245746 control chromosomes (gnomAD). c.3991C>T has been reported in the literature in individuals affected with varying cancer phenotypes including colorectal (Sjursen_2010, Limburg_2011, van Lier_2012, Lavoine_2015), endometrial (Goodfellow_2015), and breast (Susswein_2016), and in individuals with a family history of Lynch syndrome (Plaschke_2006). These data indicate that the variant is very likely to be associated with disease. The variant has, however, also been reported in seemingly healthy individuals, including the father of a compound heterozygote child with Lynch Syndrome, indicating that it may exhibit reduced penetrance (Plaschke_2006). One publication reports experimental evidence indicating that the variant results in exon 9 skipping (Plaschke_2006), and multiple publications report a reduction of IHC staining for MSH6 protein in samples from individuals with this variant. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

MSH6-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 04, 2024

The MSH6 c.3991C>T variant is predicted to result in premature protein termination (p.Arg1331*). This variant has been repeatedly reported in the heterozygous state in individuals with variable cancer phenotypes, including patients with colorectal, endometrial, and breast cancer (see for example Sjursen et al. 2010. PubMed ID: 20587412; Goodfellow et al. 2015. PubMed ID: 26552419; Susswein et al. 2016. PubMed ID: 26681312). This variant has also been reported in the homozygous and compound heterozygous states in patients with constitutional mismatch repair syndrome (see for example Plaschke et al. 2006. PubMed ID: 16418736; Lavoine et al. 2015. PubMed ID: 26318770). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/42472/). Nonsense variants in MSH6 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change creates a premature translational stop signal (p.Arg1331*) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the MSH6 protein. This variant is present in population databases (rs267608094, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 16034045, 18301448, 20587412, 21056691, 21642682, 27601186). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 42472). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MSH6 function (PMID: 16418736). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (Invitae). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 19851887, 21155762). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.88

MutationTaster

Benign

1.0

D;D;D;D

Vest4

0.88

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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