2-47800075-C-G

Variant names:

• chr2-47800075-C-G
• rs63750832
• NM_000179.3:c.2092C>G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000179.3(MSH6):​c.2092C>G​(p.Gln698Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000291 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:1
• Conservation: PhyloP100: 3.66

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37297663).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.2092C>G	p.Gln698Glu	missense_variant	Exon 4 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.2092C>G	p.Gln698Glu	missense_variant	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250646 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135476

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461856 Hom.: 0 Cov.: 34 AF XY: 0.0000275 AC XY: 20 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.0000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

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: 0.0000282 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 p.Gln698Glu variant was identified in 3 of 2420 proband chromosomes (frequency: 0.001) from French, Danish and Cypriot individuals or families with Lynch Syndrome and was not identified in 100 control chromosomes from healthy individuals (Wang 1999, Nilbert 2009, Loizidou 2014). Using 2 different bioinformatics tools predicting the impact of missense variants in the MSH6 gene, it was found that variant is neutral (Terui 2013, Ali 2012). The variant was also identified in dbSNP (ID: rs63750832) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance, reviewed by an expert panel (2013); submitters: INSIGHT, Ambry Genetics, Invitae, GeneDx, and Color Genomics Inc.), Clinvitae (4x), Cosmic (1x in a breast carcinoma), UMD-LSDB (1x classified UV), Mismatch Repair Genes Variant Database (1x), and Insight Hereditary Tumors Database (1x). The variant was not identified in the COGR, MutDB, or Zhejiang Colon Cancer Databases. The variant was identified in control databases in 3 of 245362 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Latino in 1 of 33568 chromosomes (freq: 0.00003), European Non-Finnish in 2 of 110928 chromosomes (freq: 0.00002), it was not observed in the African, Other, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Gln698Glu residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSH6: PP2, BP4 -

Sep 03, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal and/or family history of colorectal cancer (PMID: 10480359, 18566915, 25133505, 32635641); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25133505, 10480359, 22290698, 23621914, 26333163, 18566915, 32635641, 31391288, 34426522, 33471991, 17531815, 21120944) -

Nov 20, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH6 c.2092C>G (p.Gln698Glu) variant has been reported in the published literature in an individual meeting revised Bethesda guidelines (PMID: 25133505 (2014), in an individual with a Lynch syndrome-related cancer (PMID: 31391288 (2020)), in two families with colorectal cancer (PMID: 10480359 (1998), 18566915 (2009)), and in one family with renal cell carcinoma (PMID: 32830346 (2021)). In a large scale breast cancer association study, this variant has been observed in 10 breast cancer cases and 4 reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.000008 (2/250646 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 conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Lynch syndrome 5 Uncertain:3

Mar 29, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 698 of the MSH6 protein (p.Gln698Glu). This variant is present in population databases (rs63750832, gnomAD 0.003%). This missense change has been observed in individual(s) with colorectal cancer and/or suspected Lynch syndrome PMID: 25133505, 10480359, 22290698, 23621914, 26333163, 18566915, 32635641, 31391288). ClinVar contains an entry for this variant (Variation ID: 89251) with 6 submissions, all of which describe it as of uncertain significance. -

May 02, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:3

Mar 04, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamine with glutamic acid at codon 698 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of having Lynch syndrome (PMID: 10480359, 25133505, 31391288, 32635641). This variant has been identified in 2/250646 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Aug 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q698E variant (also known as c.2092C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2092. The glutamine at codon 698 is replaced by glutamic acid, an amino acid with highly similar properties. In one study, this alteration was detected in 1/115 Caucasian Lynch-like syndrome patients harboring MMR deficient tumors and/or microsatellite instability (MSI) and called a variant of uncertain significance (Dámaso E et al. Cancers (Basel), 2020 Jul;12:). In another study, this alteration was reported as a variant of uncertain significance in one individual from a Danish hereditary colorectal cancer registry and was reported in an individual with colorectal cancer at age 65 from a Cypriot cohort of 77 patients fulfilling revised Bethesda guidelines (Nilbert M et al. Fam. Cancer. 2009 Jun;8:75-83; Loizidou MA et al. PLoS ONE. 2014 Aug;9:e105501). This alteration has also been reported in a familial colorectal cancer kindred (Wang Q et al. Hum. Genet. 1999;105:79-85). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Oct 27, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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

- -

Endometrial carcinoma Uncertain:1

Mar 13, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Uncertain	0.55	.;.;D;T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.047
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	.;D;D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.37	T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.5	.;.;L;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	.;N;N;.;N
REVEL	Uncertain	0.46
Sift	Benign	0.13	.;T;T;.;T
Sift4G	Benign	0.30	T;T;T;T;T
Polyphen		0.20	.;.;B;.;.
Vest4		0.57
MutPred		0.68		.;.;Gain of helix (P = 0.0225);.;.;
MVP		0.83
ClinPred		0.23	T
GERP RS		4.0
Varity_R		0.50
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs63750832; hg19: chr2-48027214; COSMIC: COSV52279974; COSMIC: COSV52279974;