2-47798867-A-T

Position:

• chr2-47798867-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000179.3(MSH6):​c.884A>T​(p.Lys295Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.884A>T	p.Lys295Ile	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>T	p.Lys295Ile	missense_variant	4/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with colorectal cancer (Raskin 2017); This variant is associated with the following publications: (PMID: 29212164) -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 30, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 14, 2024	The p.K295I variant (also known as c.884A>T), located in coding exon 4 of the MSH6 gene, results from an A to T substitution at nucleotide position 884. The lysine at codon 295 is replaced by isoleucine, an amino acid with dissimilar properties. This variant was detected in a study of 1046 familial colorectal cancer cases and 1006 unrelated controls (Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463). This variant has also been identified in probands whose Lynch syndrome-associated tumors demonstrated normal mismatch repair protein expression by immunohistochemistry (IHC) (Ambry internal data; Shirts BH et al. Genet Med, 2016 10;18:974-81). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 04, 2023

This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 295 of the MSH6 protein (p.Lys295Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biliary tract cancer and/or colorectal cancer (PMID: 26845104, 29212164, 36243179). ClinVar contains an entry for this variant (Variation ID: 187266). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	.;D;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.4	.;M;.
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.5	D;D;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.017	D;D;.
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.98	.;D;.
Vest4		0.56
MutPred		0.34		.;Loss of methylation at K295 (P = 0.003);.;
MVP		0.95
ClinPred		0.95	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.39

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;