chr2-47806651-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000179.3(MSH6):c.4001G>A(p.Arg1334Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000275 in 1,455,180 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1334P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:20

Conservation

PhyloP100: 4.10

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-47806651-G-C is described in Lovd as [Pathogenic].

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 2-47806651-G-A is Pathogenic according to our data. Variant chr2-47806651-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 89506.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47806651-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.4001G>A	p.Arg1334Gln	missense_variant, splice_region_variant	Exon 9 of 10	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 link	c.4001G>A	p.Arg1334Gln	missense_variant, splice_region_variant	Exon 9 of 10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1455180

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724216

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000361

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 15, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH6 c.4001G>A (p.Arg1334Gln) variant has been reported in the published literature in affected individuals with colorectal cancer (PMIDs: 12373605 (2002), 15236168 (2004), 17453009 (2007), 21836479 (2011), 26681312 (2015), 30264118 (2018), 31447099 (2019), and 34178123 (2021)), breast cancer (PMIDs: 26681312 (2015) and 33471991)), endometrial cancer (PMIDs: 10508506 (1999) and 15236168 (2004), 33467402 (2021)), lung cancer (PMID: 31297337 (2019)), as well as in individuals diagnosed with Lynch Syndrome (PMIDs: 18566915 (2009), 20028993 (2010), and 27601186 (2016)). It was also found in a tumor as a somatic variant (PMID: 29887214 (2018)). Functional studies have demonstrated that this variant is damaging to protein function (PMIDs: 185669115 (2009), 28531214 (2017), and 30264118 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

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

Significance: Pathogenic

Review Status: no assertion criteria provided

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

- -

Aug 10, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP3, PP4, PP5, PM2_moderate, PS4_moderate -

Feb 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21081928, 23621914, 24362816, 18566915, 12547705, 15236168, 12373605, 20028993, 18415027, 27601186, 24705251, 26681312, 28502729, 24728189, 27768684, 17453009, 30283497, 29887214, 10508506, 8063241, 21836479, 31297337, 31447099, 32719484, 21120944, 17531815, 12019211, 34178123, 30787465) -

Apr 26, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome

Pathogenic:4

Feb 04, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_MOD; PM2_SUP; PP4; PP1; PS3_SUP -

Sep 24, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G>A nucleotide substitution at the last nucleotide of exon 9 of the MSH6 gene. Splice site prediction tools suggest that this variant may impact RNA splicing. A RT-PCR analysis of RNA derived from two carriers has reported out-of-frame skipping of exon 9 (UMD database, http://139.124.156.133/4D_molecules/UMD230309.html). 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: 12547705, 17453009, 18566915, 27601186; UMD database) and in individuals affected with endometrial cancer (PMID: 33467402) and colorectal cancer (PMID: 26681312). Multifactorial likelihood model using health history, in silico, and experimental data has suggested this variant has a high probability of being pathogenic (InSiGHT database, http://insight-database.org/). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Jun 15, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg1334Gln variant in MSH6 has been reported in 4 individuals with MSH6-as sociated cancers and segregated with disease in 7 affected relatives from 2 fami lies (Hendriks 2004, Overbeek 2007, van Puijenbroek 2008, Klarskov 2011). It was absent from large population studies. This variant affects the last base of the exon, which is part of the 5? splice region and computational tools predict alt ered splicing, which is expected to lead to an altered or absent protein. Consis tent with this, tumors from patients harboring this variant showed absence of MS H6 protein (Hendriks 2004, Klarskov 2011). This variant was classified as Pathog enic on Sept 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV00 0108190.2). In summary, this variant meets criteria to be classified as pathogen ic for Lynch syndrome. ACMG/AMP criteria applied: PP1_Str, PS4_Mod, PM2, PS3_Mod , PP3 (Richards 2015). -

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Multifactorial likelihood analysis posterior probability >0.99 -

Lynch syndrome 5

Pathogenic:3

Mar 29, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. -

Aug 09, 2024

Department of Human Genetics, Hannover Medical School

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Mar 24, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4001G>A pathogenic mutation (also known as p.R1334Q), located in coding exon 9 of the MSH6 gene, results from a G to A substitution at nucleotide position 4001. The amino acid change results in arginine to glutamine at codon 1334, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 9, which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This mutation has been reported in multiple Lynch syndrome patients as well as families and this variant segregated with disease in these families (Wijnen J et al. Nat Genet. 1999;23(2):142-144; Gille et al. Br J Cancer. 2002;87(8):892-897; Overbeek LI et al. Br J Cancer. 2007;96(10):1605-1612; Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36(5):2823-2835). Functional studies have also demonstrated the pathogenicity of this variant (Houlleberghs H et al. PLoS Genet. 2017 May;13(5):e1006765). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Apr 18, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Endometrial carcinoma

Pathogenic:2

Aug 23, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 p.Arg1334Gln variant was identified in 5 of 3358 proband chromosomes (frequency: 0.001) from Dutch, Danish and Norwegian individuals or families with HNPCC (Wijnen_1999_10508506, Nilbert_2009_18566915, Gille_2002_12373605 , Hendriks_2004_15236168, Overbeek_2007_17453009). A bioinformatics tool, CoDP (Combination of the Different Properties), that integrates the prediction results of three methods, namely MAPP, PolyPhen-2 and SIFT and two other structural properties, found the variant had no impact on the MSH6 protein (Terui_2013_23621914). The variant was also identified in dbSNP (ID: rs267608122) â€šÃ„ÃºWith Likely pathogenic,Pathogenic alleleâ€šÃ„Ã¹, ClinVar (classified as pathogenic, reviewed by an expert panel(2013); submitters: pathogenic by InSIGHT and Ambry Genetics, likely pathogenic by GeneDx and uncertain significance by Mayo Clinic Genetic Testing Laboratories), Clinvitae (4x), Cosmic (1x in a glioma), UMD-LSDB (4x as causal), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database (9x). The variant was not identified in GeneInsight-COGR, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Arg1334 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Gln to the protein; this information is not very predictive of pathogenicity. The p.Arg1334Gln variant occurs in the last nucleotide of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Hereditary nonpolyposis colon cancer

Pathogenic:1

Oct 31, 2024

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.4001G>A (p.Arg1334Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 5' splicing donor site. One predicts the variant weakens this site. The variant was absent in 244224 control chromosomes (gnomAD). c.4001G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome (e.g. Wjnen_1999, Susswein_2016, Sun_2019, Yang_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 26681312, 31297337, 34178123, 10508506). ClinVar contains an entry for this variant (Variation ID: 89506). Based on the evidence outlined above, the variant was classified 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 replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1334 of the MSH6 protein (p.Arg1334Gln). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 10508506, 15236168, 17453009, 21081928, 21836479, 26681312). It has also been observed to segregate with disease in related individuals. 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: 89506). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 9 and introduces a new termination codon (internal data). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

.;.;T;T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

.;D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.57

D;D;D;D;D

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

1.7

.;.;.;L;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.9

.;N;.;N;N

REVEL

Uncertain

0.54

Sift

Benign

0.061

.;T;.;D;T

Sift4G

Benign

0.14

T;T;T;T;T

Polyphen

0.98

.;.;.;D;.

Vest4

0.56

MutPred

0.37

.;.;.;Loss of MoRF binding (P = 0.0301);.;

MVP

0.94

ClinPred

0.87

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.41

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.86

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.86

Position offset: 0

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