rs63750253

Positions:

• chr2-47803531-G-A
• chr2-47803531-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3 BP6

The NM_000179.3(MSH6):​c.3284G>A​(p.Arg1095His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1095C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:3
• Conservation: PhyloP100: 9.97

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.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836
• BP6: Variant 2-47803531-G-A is Benign according to our data. Variant chr2-47803531-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89368.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=3}. Variant chr2-47803531-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.3284G>A	p.Arg1095His	missense_variant	5/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.3284G>A	p.Arg1095His	missense_variant	5/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

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: 0.000478

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251448 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135892

Gnomad AFR exome AF: 0.0000615

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: 0.0000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.0000454 AC XY: 33 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74390

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 09, 2023	This missense variant replaces arginine with histidine at codon 1095 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). Functional studies have found this variant to be normal in in vitro mismatch DNA repair activity, complementation of MSH6-deficient mouse embryonic stem cells and MSH6 binding (PMID: 12522549, 22581703, 17594722, 24040339). This variant has been reported in individuals affected with colorectal cancer and Lynch syndrome associated cancer and/or polyps (PMID: 12522549, 25980754, 28944238) and with early-onset breast cancer (PMID: 25503501). This variant has been identified in 12/251448 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 29, 2023	The p.R1095H variant (also known as c.3284G>A), located in coding exon 5 of the MSH6 gene, results from a G to A substitution at nucleotide position 3284. The arginine at codon 1095 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a proband diagnosed with metachronous MSI-H colorectal cancer (CRC) at 65y and 74y with a family history of CRC in 3 siblings diagnosed in their 60s and 70s (Kariola R et al. Hum Genet. 2003 Feb; 112(2):105-9). However, multiple functional assays have demonstrated that this alteration has activity comparable to wild type indicating it is likely not pathogenic (Kariola R et al. Hum. Genet. 2003 Feb;112(2):105-9; Ou J et al. Hum. Mutat. 2007 Nov;28(11):1047-54; Kansikas M et al. Hum. Mutat. 2011 Jan;32(1):107-15; Wielders EA et al. PLoS One. 2013 Sep 10;8(9):e74766; Kantelinen J et al. Hum. Mutat. 2012 Aug;33(8):1294-301). This variant was also identified once in a cohort comprised of 1231 colorectal cancer cases and 93 controls (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). Based on internal structure analysis, p.R1095H strongly perturbs the structure of the ATPase domain more than a known likely pathogenic variant nearby (Warren JJ et al. Mol. Cell 2007 May;26:579-92). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 13, 2021	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 30, 2023	Variant summary: MSH6 c.3284G>A (p.Arg1095His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251448 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer (4.8e-05 vs 0.00014), allowing no conclusion about variant significance. c.3284G>A has been reported in the literature as a VUS in settings of multigene panel testing among individuals with colorectal cancer (e.g. Kariola_2013, Maxwell_2015, Wei_2016, Yurgelun_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome. At least one co-occurrence with a pathogenic variant has been observed at our laboratory (BRCA2 c.4284dupT, p.Gln1429fs), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant on mismatch repair (MMR) activity (e.g. Kantelinen_2012, Kariola_2013, Wielders_2013). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Five submitters classified the variant as uncertain significance and three classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Lynch syndrome 5 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 02, 2016	- -
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]. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 03, 2022	The frequency of this variant in the general population, 0.000088 (10/113738 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Lynch Syndrome (PMID: 25980754 (2015)), colorectal cancer (PMID: 27300552 (2016)), breast cancer (PMIDs: 25503501 (2015) and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2), and healthy individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2)). Functional studies show that this variant is not damaging to protein function (PMIDs: 12522549 (2003), 21120944 (2011), 22581703 (2012) and 24040339 (2013)). 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	Apr 07, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26333163, 23621914, 21120944, 17594722, 15354210, 22581703, 24040339, 12522549, 25980754, 25503501) -

Lynch syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

This missense variant replaces arginine with histidine at codon 1095 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). Functional studies have found this variant to be normal in in vitro mismatch DNA repair activity, complementation of MSH6-deficient mouse embryonic stem cells and MSH6 binding (PMID: 12522549, 22581703, 17594722, 24040339). This variant has been reported in individuals affected with colorectal cancer and Lynch syndrome associated cancer and/or polyps (PMID: 12522549, 25980754, 28944238) and with early-onset breast cancer (PMID: 25503501). This variant has been identified in 12/251448 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. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Pathogenic	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
Sift4G	Benign	0.14	T;T;T;D;T
Polyphen		1.0	.;.;.;D;.
Vest4		0.90
MVP		0.96
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.50
gMVP		0.90

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: rs63750253; hg19: chr2-48030670; COSMIC: COSV52274456; COSMIC: COSV52274456;