rs398123230

chr2-47803450-G-Achr2-47803450-G-Cchr2-47803450-G-T

Variant summary

Our verdict is Likely benign. Variant got -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. 15/19 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:7
• Conservation: PhyloP100: 1.06

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 16 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 id is 92576.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.3203G>A	p.Arg1068Gln	missense_variant	5/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.3203G>A	p.Arg1068Gln	missense_variant	5/10	1	NM_000179.3	P4

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

GnomAD3 exomes AF: 0.000123 AC: 31 AN: 251326 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135830

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 SAS 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

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.0000331

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

Gnomad4 AFR AF: 0.000169

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: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000230 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:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2020	This variant is associated with the following publications: (PMID: 26689913, 25503501, 23047549, 23104009, 27978560, 26845104, 22495361, 29625052) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 05, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MSH6: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 04, 2022	BP4 -

Lynch syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 15, 2020	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 14, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 28, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2022	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 29, 2017	- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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 v4.3

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
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.45	N
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.097	T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.21	T
Sift4G	Benign	0.64	T;T;T;T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs398123230; hg19: chr2-48030589; COSMIC: COSV52281753; COSMIC: COSV52281753;