2-47803450-G-A

Variant names:

• chr2-47803450-G-A
• rs398123230
• NM_000179.3:c.3203G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BP6

The NM_000179.3(MSH6):​c.3203G>A​(p.Arg1068Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1068G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:9
• Conservation: PhyloP100: 1.06
• Publications: 9 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: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 45 uncertain in NM_000179.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.096970975).
• BP6: Variant 2-47803450-G-A is Benign according to our data. Variant chr2-47803450-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92576.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000179.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.3203G>A	p.Arg1068Gln	missense	Exon 5 of 10	NP_000170.1
	MSH6	NM_001406795.1		c.3299G>A	p.Arg1100Gln	missense	Exon 6 of 11	NP_001393724.1
	MSH6	NM_001406813.1		c.3209G>A	p.Arg1070Gln	missense	Exon 5 of 10	NP_001393742.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.3203G>A	p.Arg1068Gln	missense	Exon 5 of 10	ENSP00000234420.5
	MSH6	ENST00000445503.5	TSL:1	n.*2550G>A		non_coding_transcript_exon	Exon 4 of 9	ENSP00000405294.1
	MSH6	ENST00000445503.5	TSL:1	n.*2550G>A		3_prime_UTR	Exon 4 of 9	ENSP00000405294.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000123 AC: 31 AN: 251326 AF XY: 0.000118

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000112 AC: 164 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.000103 AC XY: 75 AN XY: 727234

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.000134 AC: 149 AN: 1112008

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74418

African (AFR) AF: 0.000169 AC: 7 AN: 41522

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Oct 10, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH6 c.3203G>A (p.Arg1068Gln) variant has been reported in the published literature in individuals with colorectal cancer (PMIDs: 29625052 (2018), 26845104 (2016), 27978560 (2016), 22495361 (2012)), breast/ovarian cancer (PMIDs: 29625052 (2018), 26689913 (2015), 25503501 (2015), 23047549 (2012)), pancreatic cancer (PMIDs: 32659497 (2020), 28767289 (2017)), thyroid cancer (PMID: 29625052 (2018)), lung cancer (PMID: 26689913 (2015)), medulloblastoma (PMID: 26580448 (2015)), and individuals undergoing genetic testing (PMID: 37937776 (2023)). The frequency of this variant in the general population, 0.00028 (7/24964 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Nov 06, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26689913, 25503501, 23047549, 23104009, 27978560, 26845104, 22495361, 29625052)

Jun 07, 2013

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSH6: BP4

Nov 04, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4

Lynch syndrome Uncertain:3

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 15, 2020

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH6 c.3203G>A (p.Arg1068Gln) missense change has a maximum subpopulation frequency of 0.028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48030589-G-A). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer and microsatellite stability or normal mismatch repair immunohistochemistry in the tumor (PMID: 26845104, 27978560). It has also been reported in individuals with sporadic pancreatic ductal adenocarcinoma (PMID: 32659497, 28767289), breast cancer (PMID: 25503501), epithelial ovarian cancer (PMID: 23047549), and pediatric medulloblastoma (PMID: 26580448). Data submitted to ClinVar indicates that this variant did not segregate with disease in a family study (ClinVar Accession: SCV000186214.6). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.

Hereditary cancer-predisposing syndrome Benign:3

Aug 28, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Jan 02, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 14, 2022

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Lynch syndrome 5 Benign:2

Sep 04, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 03, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].

not specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSH6-related disorder Uncertain:1

Apr 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 c.3203G>A variant is predicted to result in the amino acid substitution p.Arg1068Gln. This variant has been reported in multiple individuals with various cancers including colorectal, breast, ovarian, thyroid, and pancreatic (see for example, Table 2, Okkels et al. 2012. PubMed ID: 22495361; Table S2, Shindo et al. 2017. PubMed ID: 28767289; Table S2, Huang et al. 2018. PubMed ID: 29625052, Table 2, Maxwell et al. 2015. PubMed ID: 25503501). It has also been reported in 0.028% of alleles in individuals of African descent in gnomAD and has conflicting interpretations ranging from benign to uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/92576/). The Arg1068 residue of the MSH6 protein is weakly conserved throughout evolution and multiple species have glutamine (Gln) at this amino acid position. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Malignant tumor of breast Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 p.Arg1068Gln variant was identified in 3 of 3116 proband chromosomes (frequency: 0.00096) from individuals or families with colorectal cancer, HNPCC, or breast cancer (Hampel 2018, Maxwell 2015, Okkels 2012). The variant was also identified in dbSNP (ID: rs398123230) as "With Uncertain significance, other allele", in ClinVar and Clinvitae (classified as likely benign by Ambry Genetics, Invitae and GeneDx; classified as uncertain significance by EGL, University of Washington, Illumina, Quest Diagnostics and Prevention Genetics), and UMD-LSDB (found to be co-occurring with a pathogenic MSH6 variant: c.2764C>T, p.Arg922X in 2 cases). The variant was not identified in COSMIC, MutDB, Insight Colon Cancer Gene Variant Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in control databases in 31 of 277070 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 7 of 24028 chromosomes (freq: 0.0003), Latino in 1 of 34386 chromosomes (freq: 0.00003), European Non-Finnish in 23 of 126620 chromosomes (freq: 0.0002); it was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Arg1068 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing; however, this information is not predictive enough to rule out pathogenicity. 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 benign role for this variant. This variant is classified as likely benign.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-0.50	N
PhyloP100		1.1
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.20
Sift	Benign	0.74	T
Sift4G	Benign	0.64	T
Polyphen		0.0010	B
Vest4		0.34
MVP		0.71
ClinPred		0.025	T
GERP RS		-1.2
Varity_R		0.17
gMVP		0.41
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs398123230; hg19: chr2-48030589; COSMIC: COSV52281753; COSMIC: COSV52281753;