chr2-47798646-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000179.3(MSH6):c.663A>C(p.Glu221Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000748 in 1,612,862 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E221K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00063 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00076 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:20O:1

Conservation

PhyloP100: -0.266

Publications

33 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031133354).

BP6

Variant 2-47798646-A-C is Benign according to our data. Variant chr2-47798646-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 89552.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00063 (96/152354) while in subpopulation AMR AF = 0.000915 (14/15294). AF 95% confidence interval is 0.000716. There are 1 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.663A>C	p.Glu221Asp	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.663A>C	p.Glu221Asp	missense_variant	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.000631

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000313

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000706

AC:

176

AN:

249320

AF XY:

0.000801

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000491

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000760

AC:

1110

AN:

1460508

Hom.:

Cov.:

AF XY:

0.000801

AC XY:

582

AN XY:

726568

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000470

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00123

AC:

106

AN:

86248

European-Finnish (FIN)

AF:

0.0000576

AC:

AN:

52124

Middle Eastern (MID)

AF:

0.000696

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.000846

AC:

941

AN:

1111972

Other (OTH)

AF:

0.000547

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

122

183

244

305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

102

136

170

<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:

0.000630

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000711

AC XY:

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41596

American (AMR)

AF:

0.000915

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000897

AC:

AN:

68028

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.000739

Hom.:

Bravo

AF:

0.000646

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000618

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:20Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:6

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MSH6: BP1, BP4, BP5 -

Apr 16, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27153395, 28767289, 17453009, 18269114, 24728327, 23621914, 26300997, 22290698, 21153778, 23047549, 26898890, 26333163, 17344846, 28531214, 28481244, 28874130, 29575718, 18301448, 31159747, 32854451) -

Oct 28, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The MSH6 c.663A>C (p.Glu221Asp) variant causes a missense change involving a non-conserved nucleotide with 5/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 75/119664 (1/1595), which is approximately 4 times the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7037 (0.0001421), suggesting this variant is likely a benign polymorphism. The variant of interest has been reported in multiple affected individuals via publications. In addition, multiple clinical diagnostic laboratories/databases cite the variant as "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign. -

Oct 12, 2017

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 08, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 28, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:6

Aug 01, 2018

GeneKor MSA

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 30, 2017

True Health Diagnostics

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 01, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jun 24, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Nov 20, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu221Asp variant is not predicted to introduce a novel splice site by any splice site algorithm. The p.Glu221Asp missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The aspartic acid residue at codon 221 of MSH6 is present in Prairie vole and 2 other mammalian species. The nucleotide c.663 in MSH6 is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Benign. -

Oct 09, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:3Other:1

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 15, 2021

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lynch syndrome 5

Uncertain:2Benign:1

May 01, 2019

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Dec 19, 2024

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Abnormality of the ovary

Uncertain:1

Aug 16, 2021

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Carcinoma of colon

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MSH6 p.Glu221Asp variant was identified in 7 of 1567 proband chromosomes (frequency: 0.004) from individuals or families with colorectal cancer (Devlin 2008, Steinke 2008, Bodian 2014, Liccardo 2017, Overbeek 2007, Simbolo 2015). The variant was also identified in dbSNP (ID: rs41557217) as "With Uncertain significance, other allele ", ClinVar (classified as benign by Invitae, Ambry Genetics and one clinical laboratory; as likely benign by GeneDx and four clinical laboratories; as uncertain significance by tree submitters), COGR, Cosmic (1x in Haematopoietic and lymphoid tissue), MutDB, UMD-LSDB (3x as unclassified variant), Mismatch Repair Genes Variant Database (1x), and in Insight Hereditary Tumors Database (2x VUS). The variant was not identified in Zhejiang University Database. The variant was identified in control databases in 189 of 275098 chromosomes at a frequency of 0.0007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 6 of 23956 chromosomes (freq: 0.0003), Other in 3 of 6442 chromosomes (freq: 0.0005), Latino in 12 of 34380 chromosomes (freq: 0.0003), European in 133 of 126092 chromosomes (freq: 0.001), East Asian in 1 of 18824 chromosomes (freq: 0.00005), Finnish in 1 of 24524 chromosomes (freq: 0.00004), and South Asian in 33 of 30752 chromosomes (freq: 0.001), while the variant was not observed in the Ashkenazi Jewish population. The p.Glu221 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In addition, in functional assay using oligonucleotide-directed mutagenesis screen the variant was not identified as MMR abrogating; the variant was found in patients who also harbored a second, known pathogenic mutation in one of the DNA MMR genes that was likely causative for the LS phenotype (Houlleberghs 2017). The p.Glu221Asp was also detected in a second patient who was 83 years old and did not have a family history suspicious for LS. The observation of this variant with a co-occurring pathogenic variant (MLH1, EXON05-8, c.381-?_677del+?) by our laboratory increases the likelihood this variant does not have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Breast and/or ovarian cancer

Benign:1

May 17, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer

Benign:1

Jan 23, 2024

Mendelics

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

0.081

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.23

CADD

Benign

9.7

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

.;T;T;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.64

T;T;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.031

T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.6

.;L;.;.

PhyloP100

-0.27

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.87

N;N;.;N

REVEL

Uncertain

0.32

Sift

Benign

0.16

T;T;.;T

Sift4G

Benign

0.42

T;T;T;D

Polyphen

0.0030

.;B;.;.

Vest4

0.17

MutPred

0.092

.;Gain of relative solvent accessibility (P = 0.09);.;.;

MVP

0.84

ClinPred

0.0068

GERP RS

-0.72

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

3.2

Varity_R

0.032

gMVP

0.073

Mutation Taster

=90/10

polymorphism

(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