rs61754783

chr2-47799457-A-Gchr2-47799457-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000179.3(MSH6):c.1474A>G(p.Met492Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M492T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:1
• Conservation: PhyloP100: 9.29

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.1474A>G	p.Met492Val	missense_variant	4/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.1474A>G	p.Met492Val	missense_variant	4/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000796 AC: 20 AN: 251172 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135734

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: 0.000462

Gnomad NFE exome AF: 0.0000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000104 AC: 152 AN: 1461870 Hom.: 0 Cov.: 34 AF XY: 0.000111 AC XY: 81 AN XY: 727230

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: 0.000562

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74346

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.0000604

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 22, 2023	In the published literature, this variant has been identified in individuals with Lynch syndrome (PMID: 22495361 (2012), 18566915 (2009), 12658575 (2003)), ovarian cancer (PMID: 23047549 (2012)), and pancreatic cancer (PMID: 28767289 (2017)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as unaffected individuals (see LOVD (http://databases.lovd.nl/shared/genes/MSH6) and PMID: 33471991 (2021)). An in vitro functional study has reported that this variant causes a slight reduction in mismatch repair activity (PMID: 22102614 (2012)). The frequency of this variant in the general population, 0.00048 (12/25118 chromosomes in European (Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 15, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: mismatch repair activity comparable to wild-type (Drost et al., 2012); Identified in individuals with Lynch syndrome-associated and other cancers (Wagner et al., 2003; Nilbert et al., 2009; Okkels et al., 2012; Pal et al., 2012; Shindo et al., 2017; Yehia et al., 2018); This variant is associated with the following publications: (PMID: 23047549, 26333163, 23621914, 12658575, 18566915, 22495361, 28767289, 29684080, 29899834, 31391288, 31422818, 17531815, 21120944, 22102614, 33471991) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 30, 2016	The p.Met492Val variant in MSH6 has been reported in 4 individuals with Lynch sy ndrome-related cancers (Wagner 2003, Okkels 2012, Pal 2012). In vitro functional studies provide some evidence that the p.Met492Val variant may not impact prote in function (Drost 2012). However, these types of assays may not accurately repr esent biological function. This variant has been identified in 3/6610 Finnish ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs61754783). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In addit ion, this variant was classified as a Variant of Uncertain Significance on Sep 5 , 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107859.2). In summary, the clinical significance of the p.Met492Val variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 06, 2023	This missense variant replaces methionine with valine at codon 492 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not affect MSH6 mismatch repair activity (PMID: 22102614). This variant has been reported in individuals with Lynch syndrome (PMID: 12658575, 18566915, 22495361), in an individual affected with ovarian cancer (PMID: 23047549), and in an individual affected with pancreatic neuroendocrine tumor (PMID: 28767289). This variant occurs at an elevated frequency in the general population and has been identified in 23/282572 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 08, 2024	The p.M492V variant (also known as c.1474A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1474. The methionine at codon 492 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported as a variant of unknown significance in multiple individuals, including one family from the Danish HNPCC-registry (Nilbert M et al. Fam. Cancer. 2009 Jun;8:75-83), one family meeting Amsterdam criteria (Wagner A et al. Am. J. Hum. Genet. 2003 May;72:1088-100), two unrelated individuals from HNPCC families with colon tumors demonstrating normal MSH6 expression on IHC studies (Okkels H et al. Appl. Immunohistochem. Mol. Morphol. 2012 Oct;20:470-7), and a patient diagnosed with a pancreatic neuroendocrine tumor at age 57 (Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390). In addition, one functional study reported this variant to be proficient in in vitro mismatch repair (MMR) activity (Drost M et al. Hum. Mutat. 2012 Mar;33:488-94). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Carcinoma of colon Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Met492Val variant was identified in 2 of 2234 proband chromosomes (frequency: 0.001) from families with Lynch syndrome (Nilbert 2009, Wagner 2003); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs61754783) “With Uncertain significance allele”, HGMD, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, ClinVar database (classified as having uncertain significance by the InSiGHT expert review panel), and UMD (1X as an unclassified variant). An in vitro functional study by Drost (2011) demonstrated that the variant had similar mismatch repair efficiency to wild type MSH6, and an in silico study analyzing structural properties suggests that the variant has no impact on the MSH6 protein (Terui 2013).The p.Met492 residue is conserved in mammals but not across all lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information 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 unknown significance. -

Lynch syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 15, 2023

This missense variant replaces methionine with valine at codon 492 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not affect MSH6 mismatch repair activity (PMID: 22102614). This variant has been reported in individuals with Lynch syndrome (PMID: 12658575, 18566915, 22495361), in an individual affected with ovarian cancer (PMID: 23047549), and in an individual affected with pancreatic neuroendocrine tumor (PMID: 28767289). This variant occurs at an elevated frequency in the general population and has been identified in 23/282572 chromosomes 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. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.73	D;D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
Sift4G	Uncertain	0.041	D;D;D;D;D
Polyphen		0.77	.;.;P;.;.
Vest4		0.76
MVP		0.93
ClinPred		0.25	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.85
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs61754783; hg19: chr2-48026596;