chr2-47799265-A-G

Position:

• chr2-47799265-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3 PP4 PM2_Supporting PS3

This summary comes from the ClinGen Evidence Repository: The MSH6 c.1282A>G variant is predicted as a missense p.(Lys428Glu) variant. Its MAPP+PolyPhen-2 prior probability for pathogenicity is >0.68 & ≤0.81 (http://priors.hci.utah.edu/PRIORS). It is extremely rare in gnomAD v2.1.1 non-cancer dataset and gnomAD v4.1 (<1 in 50,000 alleles: <0,002%). Functional defect was demonstrated by CIMRA assay (Functional Odds for Pathogenicity >18.7; Insight database). It was identified in an individual affected by colon cancer showing MSH6 loss (Insight database). Therefore, this variant is classified as likely pathogenic. (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA067440/MONDO:0005835/138

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MSH6 ENST00000234420.11 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 6.99

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_pathogenic. Variant got 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.1282A>G	p.Lys428Glu	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.1282A>G	p.Lys428Glu	missense_variant	4/10	1	NM_000179.3	ENSP00000234420	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251312 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135832

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461812 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

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: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 10, 2022	The p.K428E pathogenic mutation (also known as c.1282A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1282. The lysine at codon 428 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been identified in an individual diagnosed with colorectal cancer at 41 (Hansen MF et al. Clin Genet, 2017 Oct;92:405-414). This mutation was also found and in multiple probands whose Lynch syndrome-associated tumors demonstrated high microsatellite instability (MSI-H) and/or isolated loss of MSH6 staining on immunohistochemistry, at least one of whom met Amsterdam criteria (Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 29, 2018	- -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 455128). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 28195393, 31297992). This variant is present in population databases (rs761822293, gnomAD 0.0009%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 428 of the MSH6 protein (p.Lys428Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.80	.;.;D;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.5	.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.9	.;D;D;.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;.;D;.;.
Vest4		0.85
MutPred		0.75		.;.;Loss of methylation at K428 (P = 0.0076);.;.;
MVP		0.97
ClinPred		0.96	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.91

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: rs761822293; hg19: chr2-48026404;