NM_000179.3:c.854G>T

Variant names:

Variant summary

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

The NM_000179.3(MSH6):c.854G>T(p.Ser285Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:1

Conservation

PhyloP100: 3.64

Variant links:

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]

MSH6 links:

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]

FBXO11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.854G>T	p.Ser285Ile	missense_variant	Exon 4 of 10	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 link	c.854G>T	p.Ser285Ile	missense_variant	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251154

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135752

show subpopulations

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727240

show subpopulations

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:

0.0000207

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

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:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000423

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Apr 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S285I variant (also known as c.854G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 854. The serine at codon 285 is replaced by isoleucine, an amino acid with dissimilar properties. This variant was reported in the blood and tumor of an individual with a personal and family history colorectal cancer and was not detected in 199 controls (Kolodner RD et al. Cancer Res. 1999 Oct;59:5068-74). A functional study analyzed MSH6 missense alterations to determine their effect on biochemical activity of the MSH2-MSH6 heterodimer, this variant did not have a hydrolysis defect, suggesting that adenosine nucleotide processing is not disrupted (Cyr JL et al. J. Biol. Chem. 2008 Nov;283:31641-8). Another functional study determined that sub-cellular localization of the protein derived from this variant was comparable to wild-type, suggesting a proper MSH6 nuclear import (Belvederesi L et al. Fam. Cancer. 2012 Dec;11:675-80). However, another study reports that this variant showed a significant defect in nuclear localization as it is located within the general region of the nuclear localization signals, suggesting that cellular distribution may contribute to carcinogenesis (Gassman NR et al. PLoS ONE. 2011;6:e17907). This alteration was not found to affect mismatch repair function on an in-vitro assay measuring cells survival in response to DNA damaging agent 6-thioguanine exposure (Houlleberghs H et al. PLoS Genet. 2017 May;13:e1006765). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Aug 10, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Nov 28, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with isoleucine at codon 285 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies investigating ATP binding, ATPase activity, mismatch repair activity, and nuclear localization have provided inconsistent results (PMID: 18790734, 21437237, 22851212, 28531214). This variant has been reported in at least one individual affected with colorectal cancer (PMID: 10537275, 22851212), and an individual with unspecified cancer (PMID: 31391288). This variant has been identified in 2/251154 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. -

Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3

Uncertain:1

Mar 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Jan 17, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH6 c.854G>T (p.Ser285Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251154 control chromosomes (gnomAD). c.854G>T has been reported in the literature in at least one individual affected with familial colorectal cancer (Kolodner_1999). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Several publications report experimental evidence evaluating an impact on protein function, with conflicting results. The variant protein demonstrated modestly reduced ATPase activity, but does not appear to to alter DNA binding or DNA mismatch repair (e.g. Cyr_2008, Houlleberghs_2017). Studies assessing an impact on nuclear localization are conflicting (e.g. Gassman_2011, Belvederesi_2012). Evaluation of CRC tumor tissue from a patient with the variant showed loss of heterozygosity of the wild-type allele, but only low levels of microsatellite instability (Kolodner_1999). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS. -

Colorectal cancer

Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Lynch syndrome

Uncertain:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with isoleucine at codon 285 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies investigating ATP binding, ATPase activity, mismatch repair activity, and nuclear localization have provided inconsistent results (PMID: 18790734, 21437237, 22851212, 28531214). This variant has been reported in at least one individual affected with colorectal cancer whose tumor showed low microsatellite instability (PMID: 10537275, 22851212), and an individual with unspecified cancer (PMID: 31391288). This variant has been identified in 2/251154 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. -

not provided

Uncertain:1

Feb 24, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colon cancer or colon polyps (Kolodner et al., 1999; Tsai et al., 2019); Published functional studies are conflicting: does not affect nuclear transport of MSH6 nor ATP hydrolysis and is not resistant to DNA damaging agents, but does exhibit a decreased ability to bind ATP and alters subcellular localization (Cyr et al., 2008; Gassman et al., 2011; Belvederesi et al., 2012; Houlleberghs et al., 2017); This variant is associated with the following publications: (PMID: 23621914, 22851212, 28531214, 25637381, 10537275, 21437237, 18790734, 27899619, 26333163, 11900875, 30787465, 34445333, 30374176) -

Endometrial carcinoma

Uncertain:1

Jan 09, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Nov 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

.;D;T

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.83

T;T;T

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.60

D;D;D

MetaSVM

Uncertain

0.10

MutationAssessor

Uncertain

2.1

.;M;.

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.6

D;N;.

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0040

D;D;.

Sift4G

Benign

0.061

T;D;T

Polyphen

0.70

.;P;.

Vest4

0.48

MVP

0.91

ClinPred

0.72

GERP RS

4.3

Varity_R

0.14

gMVP

0.23

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over