2-47806231-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000179.3(MSH6):c.3674C>T(p.Thr1225Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T1225K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:13B:2

Conservation

PhyloP100: 7.51

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

intellectual developmental disorder with dysmorphic facies and behavioral abnormalities
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

FBXO11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 53 uncertain in NM_000179.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.3674C>T	p.Thr1225Met	missense_variant	Exon 8 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.3674C>T	p.Thr1225Met	missense_variant	Exon 8 of 10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000756

AC:

AN:

251248

AF XY:

0.0000884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1461712

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.0000447

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000531

AC:

AN:

1111890

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000112

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41528

American (AMR)

AF:

0.000196

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000766

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:13Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 26, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in individuals with colorectal or endometrial cancer, including some with tumor studies demonstrating results inconsistent with pathogenic variants in this gene (PMID: 10508506, 16885385, 17312306, 18566915, 22102614, 28531214, 35904628, 35223509); 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: 27601186, 10508506, 22102614, 17312306, 18566915, 16885385, 23621914, 26333163, 17531815, 21120944, 12019211, 33726816, 34598035, 30982232, 32091409, 26689913, 24448499, 32547938, 29945567, 35449176, 35223509, 28531214, 35904628, 36243179, 34326862) -

Feb 06, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MSH6 c.3674C>T (p.Thr1225Met) variant has been reported in the published literature in individuals with a personal and/or family history of colorectal cancer (PMIDs: 10508506 (1999), 17312306 (2007), 18566915 (2009), 27601186 (2016), 35904628 (2022), 35223509 (2022)), endometrial cancer (PMIDs: 16885385 (2006), 28531214 (2017)), pancreatic cancer (PMID: 29945567 (2018)), and breast cancer (PMIDs: 30982232 (2019), 33471991 (2021) see also LOVD Shared (https://databases.lovd.nl/), 35449176 (2022)). Additionally, this variant has been reported in at least one reportedly healthy individual (PMIDs: 24448499 (2014), 33471991 (2021) see also LOVD Shared (https://databases.lovd.nl/), 36243179 (2022)). Functional studies describe the variant having a neutral effect on MMR activity (PMIDs: 22102614 (2012), 28531214 (2017)). The frequency of this variant in the general population, 0.00013 (17/129030 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Uncertain:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Classification criteria: PP3, BS3 -

Dec 07, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 13, 2024

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.3674C>T (p.Thr1225Met) results in a non-conservative amino acid change located in the C-terminal region (IPR000432) and ATPase domain (Houlleberghs_MSH6_PLOS Genetics_2017) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251248 control chromosomes, predominantly at a frequency of 0.00012 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 slightly less than the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), suggesting that the variant might be a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.3674C>T, has been reported in the literature in individuals affected with Lynch Syndrome, colorectal cancer or other cancers, without strong evidence for causality (examples: Wijnen 1999, Hampel_2006, Nilbert_2009, Lagerstedt-Robinson_2007 and 2016, Bhai_2021, Djursby_2022, Fanale_2022, Okawa_2023). An endometrial tumor sample from one patient showed microsatellite instability but showed retention of MSH6 and MSH2 and loss of MLH1/PMS2 with MLH1 promoter hypermethylation (Hampel_2006). Thus these data do not allow any conclusion about variant significance. At least two publications reported experimental evidence evaluating an impact on protein function, and showed no damaging effect of this variant (Drost 2011, Houlleberghs 2017). The following publications have been ascertained in the context of this evaluation (PMID: 22102614, 16885385, 28531214, 27601186, 17312306, 18566915, 26333163, 30982232, 10508506, 29945567, 34326862, 35904628, 35223509, 36243179). ClinVar contains an entry for this variant (Variation ID: 89443). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Sep 10, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T1225M variant (also known as c.3674C>T), located in coding exon 8 of the MSH6 gene, results from a C to T substitution at nucleotide position 3674. The threonine at codon 1225 is replaced by methionine, an amino acid with similar properties. This variant has been identified in multiple high-risk colorectal/endometrial cancer patients (Wijnen J et al. Nat. Genet., 1999 Oct;23:142-4; Hampel H et al. Cancer Res., 2006 Aug;66:7810-7; Lagerstedt Robinson K et al. J. Natl. Cancer Inst., 2007 Feb;99:291-9; Nilbert M et al. Fam Cancer, 2009 Jun;8:75-83). However, functional analyses have demonstrated near-wild-type mismatch repair activity for the p.T1225M allele (Drost M et al. Hum Mutat., 2012 Mar;33:488-94; Houlleberghs H et al. PLoS Genet, 2017 May;13:e1006765). 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. -

Feb 12, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces threonine with methionine at codon 1225 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 shown that this variant does not affect MSH6 protein mismatch repair function or result in DNA damage resistance (PMID: 22102614, 28531214). This variant has been reported in individuals affected with Lynch syndrome (PMID: 10508506, 18566915, 27601186), endometrial cancer (PMID: 16885385), head and neck squamous cell carcinoma (PMID: 34598035) and breast cancer (PMID: 30982232, 32547938). This variant has also been observed in an individual affected with colorectal cancer, whose tumor showed microsatellite stability and normal MSH6 protein expression (PMID: 17312306). This variant has been identified in 22/282650 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. -

Lynch syndrome 5

Uncertain:1Benign:1

Aug 19, 2016

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 07, 2025

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 27363726]. -

Ovarian cancer

Pathogenic:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:clinical testing

- -

Lynch syndrome

Uncertain:1

Aug 23, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Malignant tumor of breast

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MSH6 p.Thr1225Met variant was identified in 8 of 11332 proband chromosomes (frequency: 0.0007) from individuals or families with HNPCC, Lynch syndrome, endometrial cancer, or prostate adenocarcinoma (Hampel 2006, Lagerstedt-Robinson 2007, Lagerstedt-Robinson 2016, Lu 2015, Nilbert 2009). The variant was also identified in dbSNP (ID: rs63750370) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and three other submitters), Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors Database (2x). The variant was not identified in the COGR, Cosmic, MutDB, UMD-LSDB, or the Zhejiang University database. The variant was identified in control databases in 24 of 276978 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 19 of 126534 chromosomes (freq: 0.0002), East Asian in 1 of 18864 chromosomes (freq: 0.00005), Finnish in 1 of 25784 chromosomes (freq: 0.00004), and South Asian in 3 of 30782 chromosomes (freq: 0.0001); it was not observed in the African, Other, Latino, and Ashkenazi Jewish, populations. The p.Thr1225 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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 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. -

Endometrial carcinoma

Uncertain:1

Feb 19, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Jan 29, 2025

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

0.24

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.27

.;.;T;D;.

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

.;D;D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.74

D;D;D;D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

0.58

.;.;.;N;.

PhyloP100

7.5

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.3

.;D;.;D;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

.;D;.;D;D

Sift4G

Pathogenic

0.0010

D;D;T;D;D

Polyphen

1.0

.;.;.;D;.

Vest4

0.83

MVP

0.91

ClinPred

0.91

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.81

Mutation Taster

=6/94

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over