rs564434147

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1BP6

The NM_000179.3(MSH6):c.4004A>C(p.Glu1335Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000522 in 1,590,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. E1335D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:5

Conservation

PhyloP100: 7.23

Publications

9 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 1 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 44 uncertain in NM_000179.3

BP6

Variant 2-47806781-A-C is Benign according to our data. Variant chr2-47806781-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 141327.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.4004A>C	p.Glu1335Ala	missense_variant, splice_region_variant	Exon 10 of 10	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9
FBXO11	NM_001190274.2 link	c.*1337T>G		downstream_gene_variant		ENST00000403359.8	NP_001177203.1	Q86XK2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 link	c.4004A>C	p.Glu1335Ala	missense_variant, splice_region_variant	Exon 10 of 10	1	NM_000179.3	ENSP00000234420.5		P52701-1
FBXO11	ENST00000403359.8 link	c.*1337T>G		downstream_gene_variant		1	NM_001190274.2	ENSP00000384823.4		Q86XK2-1

Frequencies

GnomAD3 genomes

AF:

0.0000537

AC:

AN:

149114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000267

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000629

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000486

GnomAD2 exomes

AF:

0.0000866

AC:

AN:

242576

AF XY:

0.0000915

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000212

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000451

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1441360

Hom.:

Cov.:

AF XY:

0.0000697

AC XY:

AN XY:

717184

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32588

American (AMR)

AF:

0.000187

AC:

AN:

42688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25824

East Asian (EAS)

AF:

0.00

AC:

AN:

39586

South Asian (SAS)

AF:

0.000348

AC:

AN:

83236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51990

Middle Eastern (MID)

AF:

0.000528

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.0000264

AC:

AN:

1100148

Other (OTH)

AF:

0.000101

AC:

AN:

59614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

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:

0.0000536

AC:

AN:

149224

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

72806

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40606

American (AMR)

AF:

0.000267

AC:

AN:

15008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3448

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.000630

AC:

AN:

4760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9838

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67128

Other (OTH)

AF:

0.000481

AC:

AN:

2078

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:

0.00

Hom.:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign: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.Glu1335Ala variant was identified in 3 of 680 proband chromosomes (frequency: 0.004) from individuals or families with Lynch syndrome, astrocytoma, and breast or ovarian cancer and was not identified in 694 control chromosomes from healthy individuals (Perez-Cabornero 2013, Rodriguez-Hernandez 2013, Cock-Rada 2018). The variant was also identified in dbSNP (ID: rs564434147 as "With Uncertain significance allele"), ClinVar (6x as uncertain significance by Ambry Genetics, Invitae, Counsyl, GeneDx, Color Genomics, and EGL Genetic), and UMD-LSDB (1x as unclassified variant). The variant was not identified in the COGR, Cosmic, MutDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in control databases in 18 of 237668 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 7 of 32242 chromosomes (freq: 0.0002), European Non-Finnish in 2 of 108812 chromosomes (freq: 0.00008), and South Asian in 9 of 28764 chromosomes (freq: 0.0003); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Glu1335 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. -

Feb 04, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 18, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23523604, 28528518, 24073290) -

Nov 05, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MSH6 c.4004A>C (p.Glu1335Ala) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMID: 28528518 (2017), 32547938 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)), colorectal cancer (PMID: 23523604 (2013)), astrocytoma (PMID: 24073290 (2013)), and suspected of Lynch syndrome (PMID: 31391288 (2020)). This variant has also been identified in reportedly healthy individuals (PMID: 35534704 (2022), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.00031 (9/28634 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome

Uncertain:3Benign:1

Jan 02, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glutamic acid with alanine at codon 1335 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 23523604), astrocytoma (PMID: 24073290), breast and/or ovarian cancer (PMID: 28528518, 32547938) or suspected of having Lynch syndrome (PMID: 31391288). In a large breast cancer case control study, this variant was reported in 2/60466 cases and 4/53461 unaffected controls (PMID: 33471991). This variant has also been identified in 22/271900 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. -

Sep 16, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4, BP5 c.4004A>C, located in exon 10 of the MSH6 gene, is predicted to result in the substitution of glutamic acid by alanine at codon 1335, p.(Glu1335Ala). This variant is found in 10/257458 alleles at a frequency of 0.008% in the gnomAD v2.1.1 database, non-cancer dataset. Computational tools for this variant suggest no significant impact on splicing and does not affect the protein function (MAPP+PolyPhen-2 prior probability for pathogenicity: 0.10) (BP4). To our knowledge, well-established functional studies have not been reported for this variant. It has been reported in at least 3 colorectal cancer samples with microsatellite stability and/or no consistent loss of MMR protein expression (PMID:23523604 and internal data). This variant has been reported in the ClinVar database (10x uncertain significance, 2x likely benign) and in LOVD (classified 1x uncertain significance, 1x likely benign), but it has not been classified by InSiGHT. Based on currently available information, the variant c.4004A>C should be considered a likely benign variant. -

Feb 25, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E1335A variant (also known as c.4004A>C), located in coding exon 10 of the MSH6 gene, results from an A to C substitution at nucleotide position 4004. The glutamic acid at codon 1335 is replaced by alanine, an amino acid with dissimilar properties. This variant was reported in one family that met Amsterdam criteria and segregated with disease. The proband was diagnosed with colon cancer at age 42; however, tumor testing showed wild-type BRAF analysis, microsatellite stability, and normal IHC staining (Pérez-Cabornero L et al. J Mol Diagn. 2013 May;15(3):380-90). This alteration has also been reported as a variant of unknown significance, detected in a low-grade malignant astrocytoma that showed microsatellite stability and loss of staining for MLH1, MSH2, and MSH6 on IHC (Rodríguez-Hernández I et al. PLoS One. 2013 Sep 20;8(9):e76401). This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Bonache S et al. J Cancer Res Clin Oncol, 2018 Dec;144:2495-2513; Cock-Rada AM et al. Fam Cancer, 2018 Jan;17:23-30; Nikitin AG et al. Front Oncol. 2020 May;10:666; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence for this variant is conflicting at this time, the clinical significance of this alteration remains unclear. -

Nov 03, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Lynch syndrome 5

Uncertain:2Benign:1

Jan 09, 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]. -

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 25, 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. -

MSH6-related disorder

Uncertain:1

Jan 30, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MSH6 c.4004A>C variant is predicted to result in the amino acid substitution p.Glu1335Ala. This variant has been reported in individuals with a history of Lynch syndrome, astrocytoma, and breast and/or ovarian cancer (Rodríguez-Hernández et al. 2013. PubMed ID: 24073290; Pérez-Cabornero et al. 2013. PubMed ID: 23523604; Cock-Rada et al. 2018. PubMed ID: 28528518). This variant is reported in 0.031% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/141327/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Endometrial carcinoma

Uncertain:1

Mar 13, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 26, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MSH6 c.4004A>C (p.Glu1335Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.2e-05 in 1590584 control chromosomes, predominantly at a frequency of 0.00036 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch syndrome (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.4004A>C has been reported in the literature in individuals undergoing multigene panel testing for hereditary cancers such as Lynch, low grade astrocytoma and breast (example, Perez-Cabornero_2013, Rodriguez-Hernandez_2013, Cock-Rada_2017, Nikitin_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least three co-occurrences with other pathogenic variant(s) have been reported in the literature and observed at our laboratory (BRCA1 c.5266dupC, p.Gln1756Profs, Nikitin_2020; PALB2 c.1317delG, p.Phe440fs, internal testing; CDH1 c.537delA , p.Lys179Asnfs*36, internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A study that computed a tumor characteristic likelihood ratio (TCLR) in combination with in-silico predictors and multifactorial variant prediction (MVP) model including allele frequency, co-occurrence, co-segregation, clinical and family history information classified this variant a "likely benign". The following publications have been ascertained in the context of this evaluation (PMID: 30306255, 28528518, 31391288, 32547938, 23523604, 24073290). ClinVar contains an entry for this variant (Variation ID: 141327). Some submitters cite overlapping but not identical evidences utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Feb 02, 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

0.12

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.10

.;.;T;T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

0.069

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

.;D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.090

T;T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.6

.;.;.;L;.

PhyloP100

7.2

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.82

.;N;.;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.63

.;T;.;T;T

Sift4G

Benign

0.66

T;T;T;T;T

Polyphen

0.012

.;.;.;B;.

Vest4

0.51

MutPred

0.42

.;.;.;Gain of MoRF binding (P = 0.0363);.;

MVP

0.88

ClinPred

0.12

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.47

Mutation Taster

=61/39

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.25

Position offset: 3

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