rs779617676

Positions:

chr2-47803474-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 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:6U:4

Conservation

PhyloP100: 9.97

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:

MSH6 (HGNC:):

MSH6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-47803473-C-T is described in Lovd as [Likely_pathogenic].

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 id is 186361.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3 linkuse as main transcript	c.3227G>A	p.Arg1076His	missense_variant	5/10	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 linkuse as main transcript	c.3227G>A	p.Arg1076His	missense_variant	5/10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251346

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135850

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:

0.00000479

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

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:6Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 19, 2023	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). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 11, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 23, 2024	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 17, 2024	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 in affected individuals, observed as both germline and assumed somatic occurrences; however, co-occurrence and cosegregation data are very limited (Caminsky_2016, Liu_2014, Maxwell_2016, Li_2020, Shindo_2017). These data do not allow any conclusion about variant significance. Two publications report experimental evidence evaluating an impact on protein function, however, none of these studies allows convincing conclusions about the variant effect (Seshagiri_2012, Schrader_2016). 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 uncertain significance. -
Uncertain significance, flagged submission	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Lynch syndrome

Uncertain:2

Uncertain significance, flagged submission	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	May 01, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 30, 2024	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. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 08, 2022

- -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. 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; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Endometrial carcinoma

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 15, 2023

- -

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

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;.

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

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