rs779617676

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM5PP3PP5

The NM_000179.3(MSH6):c.3227G>A(p.Arg1076His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1076C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:3

Conservation

PhyloP100: 9.97

Publications

20 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 4 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-47803473-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 89357.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.798

PP5

Variant 2-47803474-G-A is Pathogenic according to our data. Variant chr2-47803474-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 186361.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.3227G>A	p.Arg1076His	missense_variant	Exon 5 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 link	c.3227G>A	p.Arg1076His	missense_variant	Exon 5 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251346

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.418

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

Cov.:

Alfa

AF:

0.0000170

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Sep 11, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MSH6 c.3227G>A (p.Arg1076His) variant has been reported in the published literature in numerous individuals/families with Lynch syndrome (PMIDs: 37088804 (2023), 31391288 (2020), 24710284 (2014)), colorectal cancer (PMID: 31997046 (2020)), breast/ovarian cancer (PMIDs: 29263802 (2016), 26898890 (2016), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)), and pancreatic cancer (PMIDs: 32659497 (2020), 28767289 (2017)). A different variant at this codon, c.3226C>T (p.Arg1076Cys), has been reported in individuals with Lynch syndrome (PMIDs: 26832770 (2016), 27601186 (2016)) with damaging effects on MSH6 protein function (PMID: 22250089 (2012)). The frequency of the c.3227G>A (p.Arg1076His) variant in the general population, 0.000008 (2/251346 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, this variant is classified as likely pathogenic. -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 08, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

May 09, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with histidine at codon 1076 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome, pancreatic, colorectal, and breast and/or ovarian cancers (PMID: 24710284, 26898890, 27153395, 28767289, 29263802, 31997046, 37088804; ClinVar: SCV000216699.8; communication with external laboratory). Different variants occurring at the same codon, c.3226C>T (p.Arg1076Cys) and c.3226C>G (p.Arg1076Gly), are well-documented pathogenic mutations (ClinVar Variation ID: 89357, 428337). This variant has been identified in 2/251346 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Sep 11, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R1076H variant (also known as c.3227G>A), located in coding exon 5 of the MSH6 gene, results from a G to A substitution at nucleotide position 3227. The arginine at codon 1076 is replaced by histidine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals whose Lynch syndrome-associated tumors displayed isolated loss of MSH6 on immunohistochemistry (IHC) and/or had high microsatellite instability (MSI-H) (Ambry internal data). This alteration was reported in one family from a cohort of 59 Asian families meeting Amsterdam I or Amsterdam II criteria (Liu Y et al. PLoS ONE. 2014 Apr;9:e94170). This alteration has also been reported in multiple patients with a personal/family history of breast and/or ovarian cancer and patients with pancreatic cancer (Wong ESY et al. NPJ Genom. Med. 2016 Jan 13;1:15003; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-817; Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390; Hu H et al. J Am Coll Surg. 2020 11;231:527-535.e14). Another alteration at the same amino acid position, p.R1076C, has been reported as likely pathogenic due to its identification in individuals with clinical features of hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome and constitutional mismatch repair deficiency (CMMRD) syndrome (Plaschke J et al. Eur. J. Hum. Genet. 2006 May;14:561-6; Okkels H et al. Int J Colorectal Dis. 2006 Dec;21:847-50; Rahner N et al. Am. J. Med. Genet. A. 2008 May;146A:1314-9; Schofield L et al. Int. J .Cancer. 2009 Sep;125:1492-3; Jasperson KW et al. Clin. Genet. 2011 Oct;80:394-7; Gardès P et al. J. Immunol. 2012 Feb;188:2023-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Jan 23, 2024

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lynch syndrome

Uncertain:2

May 30, 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 arginine with histidine at codon 1076 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome, pancreatic, colorectal, and breast and/or ovarian cancers (PMID: 24710284, 26898890, 27153395, 29263802, 28767289, 37088804; ClinVar: SCV000216699.6; communication with external laboratory). However, characterization of mutations in tumors with this variant suggest the mismatch repair phenotype may be explained by other somatic mutations (PMID: 29887214). Different variants occurring at the same codon, c.3226C>T (p.Arg1076Cys) and c.3226C>G (p.Arg1076Gly), are well-documented pathogenic mutations (ClinVar Variation ID: 89357, 428337). This variant has been identified in 2/251346 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. -

May 01, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

MSH6 NM_000179.2:c.3227G>A has a 58.2% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214. -

Hereditary nonpolyposis colon cancer

Pathogenic:1

Dec 22, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MSH6 c.3227G>A (p.Arg1076His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) 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 8e-06 in 251346 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3227G>A has been reported in the literature and at our laboratory in individuals fulfilling the Amsterdam criteria for Lynch Syndrome/ individuals meeting guidelines for hereditary cancer risk evaluation and/or features of MSH6-related cancer (Caminsky_2016, Liu_2014, Maxwell_2016, Li_2020, Shindo_2017, internal data). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22895193, 26556299, 26898890, 31391288, 24710284, 27153395, 28767289). ClinVar contains an entry for this variant (Variation ID: 186361). Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1076 of the MSH6 protein (p.Arg1076His). This variant is present in population databases (rs779617676, gnomAD 0.002%). This missense change has been observed in individuals with Lynch syndrome and/or MSH6-related conditions (PMID: 24710284, 26898890, 31997046; external communication). ClinVar contains an entry for this variant (Variation ID: 186361). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt MSH6 function with a positive predictive value of 95%. This variant disrupts the p.Arg1076 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15483016, 16418736, 16525781, 18409202, 18566915, 21039432; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma

Pathogenic:1

May 15, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

.;.;D;D;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;D;D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.80

D;D;D;D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.2

.;.;.;M;.

PhyloP100

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.8

.;D;.;D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0040

.;D;.;D;D

Sift4G

Benign

0.21

T;D;T;D;T

Polyphen

1.0

.;.;.;D;.

Vest4

0.84

MutPred

0.85

.;.;.;Loss of sheet (P = 0.0817);.;

MVP

0.93

ClinPred

0.96

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.46

gMVP

0.92

Mutation Taster

=61/39

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over