2-47798867-A-G

Position:

• chr2-47798867-A-G

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BS4_Supporting

This summary comes from the ClinGen Evidence Repository: The MSH6 c.884A>G variant results in a missense change, p.(Lys295Arg). MCAF (95% CI) is 0.013% in GnomAD v2.1.1 and Grpmax is 0.01964% in GnomAD v4.1 (below BS1 threshold). In silico predictions are inconclusive. It has found in an individual affected by CRC showing MSH6 expression (LOVD). Lack of segregation with cancer (LR: 0.7, LOVD). Nuclear localization in DLD-1 cells (PMID 21437237). Therefore, the variant is classified as variant of unknown significance. (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA016588/MONDO:0005835/138

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:7
• Conservation: PhyloP100: 3.37

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]

MSH6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got -1 ACMG points.

• BS4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.884A>G	p.Lys295Arg	missense_variant	4/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.884A>G	p.Lys295Arg	missense_variant	4/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000262

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: 0.000176

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.0000915 AC: 23 AN: 251246 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135806

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: 0.0000462

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000174 AC: 254 AN: 1461872 Hom.: 0 Cov.: 34 AF XY: 0.000171 AC XY: 124 AN XY: 727234

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: 0.0000562

Gnomad4 NFE exome AF: 0.000219

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.000128

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 21, 2024	The MSH6 c.884A>G (p.Lys295Arg) variant has been reported in the published literature in individuals affected with colorectal cancer (PMIDs: 16010685 (2005), 18566915 (2009), 26845104 (2016), 39004446 (2024)), ovarian cancer (PMIDs: 23047549 (2012), 26689913 (2015)), and uterine cancer (PMID: 34326862 (2021)). This variant has also been reported in affected and reportedly healthy individuals in a large-scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). One functional study reported this variant to have no effect on MSH6 nuclear localization (PMID: 21437237 (2011)), however, further studies are necessary to determine the effect of this variant on other MSH6 protein functions. The frequency of this variant in the general population, 0.00018 (23/129030 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 benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2021	This variant is associated with the following publications: (PMID: 21437237, 18566915, 23621914, 16010685, 26333163, 26689913, 23047549, 26845104) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH6 p.Lys295Arg variant was identified in 4 of 8180 proband chromosomes (frequency: 0.0005) from individuals or families with breast or colorectal cancer (Colley 2005, Nilbert 2009, Pal 2012, Shirts 2015). The variant was also identified in dbSNP (ID: rs267608051) as "With Uncertain significance allele ", ClinVar (classified as uncertain significance by InSight, GeneDx, Ambry Genetics, Invitae, Counsyl and five clinical laboratories), UMD-LSDB (2x as unclassified variant), Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors (2x) databases. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, or Zhejiang University, databases. The variant was identified in control databases in 26 of 276994 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 34408 chromosomes (freq: 0.00003), European in 23 of 126552 chromosomes (freq: 0.0002), Finnish in 2 of 25790 chromosomes (freq: 0.00008), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Lys295 residue is conserved in mammals 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In addition, in vitro study has shown that variant located in substantial amino-terminal region and does not disrupt MSH6 stability and localization signal. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper, no segs, ExAC: 0.02% (12/66598) European chromosomes -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2022	Variant summary: MSH6 c.884A>G (p.Lys295Arg) 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. The variant allele was found at a frequency of 9.2e-05 in 251246 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.34 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.884A>G has been reported in the literature associated with several types of cancer including but not limited to colorectal adenomas, Lynch syndrome, breast/ovarian cancer, colon cancer (Example: Lu_2015, Shirts_2015, Pal_2012, Nilbert_2009, Colley_2005, VanMarcke_2020). These reports however, do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In one ovarian cancer patient, a pathogenic BRCA2 variant was also found in the patient, providing supporting evidence for a benign role (Li_2019). One study reports that this variant did not affect MSH6 cellular localization but its proficiency in mismatch repair activity has not been addressed (Gassman_2011). 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Nine submitters classified the variant as VUS while three classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Lynch syndrome 5 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 16, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 18, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 29, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 09, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 17, 2019	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. -

Lynch syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Nov 20, 2015

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Sep 11, 2024

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;T;T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.4	.;M;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.7	N;N;.
REVEL	Uncertain	0.39
Sift	Benign	0.048	D;D;.
Sift4G	Uncertain	0.059	T;T;T
Polyphen		0.94	.;P;.
Vest4		0.22
MVP		0.92
ClinPred		0.29	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.095
gMVP		0.26

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: rs267608051; hg19: chr2-48026006;