rs41295278

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000179.3(MSH6):c.3961A>G(p.Arg1321Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000231 in 1,612,772 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).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15B:5

Conservation

PhyloP100: 3.89

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:

FBXO11 (HGNC:):

FBXO11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26330334).

BP6

Variant 2-47806611-A-G is Benign according to our data. Variant chr2-47806611-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89490.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=11, Benign=1}. Variant chr2-47806611-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3 linkuse as main transcript	c.3961A>G	p.Arg1321Gly	missense_variant	9/10	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.3961A>G	p.Arg1321Gly	missense_variant	9/10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000145

AC:

AN:

248336

Hom.:

AF XY:

0.000164

AC XY:

AN XY:

134426

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.0000580

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:

0.000277

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000237

AC:

346

AN:

1460492

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

173

AN XY:

726562

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

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:

0.000300

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000171

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000211

Hom.:

Bravo

AF:

0.000159

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:15Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lynch syndrome 5

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 29, 2023	This variant is considered 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: 25085752]. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 06, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 26, 2022	- -

not provided

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 06, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	This variant is denoted MSH6 c.3961A>G at the cDNA level, p.Arg1321Gly (R1321G) at the protein level, and results in the change of an Arginine to a Glycine (AGA>GGA). This variant has been reported in individuals with early-onset colorectal cancer (CRC), pancreatic cancer, and in one individual with a personal history of Lynch syndrome-associated cancer and/or polyps (Pinto 2006, Barneston 2008, Yurgelun 2015, Jansen 2016, Shindo 2017). This variant was also reported to co-occur with an MSH2 pathogenic deletion in a patient with mismatch repair-deficient CRC (Le 2017). MSH6 Arg1321Gly was observed at an allele frequency of 0.03% (35/124,972) in individuals of European ancestry in large population cohorts (Lek 2016). MSH6 Arg1321Gly is located within an MSH2 binding site and the ATPase domain (Kariola 2002, Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Arg1321Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 09, 2022	proposed classification - variant undergoing re-assessment, contact laboratory -

not specified

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 14, 2024	Variant summary: MSH6 c.3961A>G (p.Arg1321Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal (IPR000432) domain, comprised of the ATPase domain and the HTH (helix-turn-helix) domain, the latter being involved in dimer contacts (InterPro) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 252294 control chromosomes, predominantly at a frequency of 0.00028 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 approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014). c.3961A>G has been reported in the literature in individuals affected with Lynch Syndrome, colorectal cancer (Pinto_2006, Barneston_2008, Yurgelun_2015, Jansen_2016, Gordon_2019), Cowden/Cowden-like (CS/CS-like) or Bannayan-Riley-Ruvalcaba syndromes (Yehia 2018), Tubo-ovarian cancer (Delahunty_2022), breast cancer (Faldoni_2020, Guindalini_2022), and pancreatic cancer (Emelyanova_2024). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. 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: 25637381, 18033691, 36845387, 35263119, 24055113, 38893230, 33007869, 31422818, 35264596, 29596542, 26648449, 31391288, 26689913, 26333163, 26332594, 16940983, 28767289, 23621914, 29684080, 25980754). ClinVar contains an entry for this variant (Variation ID: 89490). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jun 25, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 20, 2023	This missense variant replaces arginine with glycine at codon 1321 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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-associated cancer and/or polyps, pancreatic, kidney, uterine, omentum cancer, breast cancer, or glioblastoma (PMID: 16940983, 18033691, 25980754, 26648449, 26689913, 28767289, 29596542, 29684080, 31422818, 31391288; DOI: 10.1101/2021.04.15.21255554, 33471991), including one case with a pathogenic MSH2 covariant (PMID: 25980754). In a large breast cancer case-control study, the variant was observed in 31/60466 cases and 37/53461 unaffected controls (PMID: 33471991). This variant has also been identified in 39/279718 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 19, 2019	This alteration is classified as likely 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. -

Lynch syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 19, 2020	The MSH6 c.3961A>G (p.Arg1321Gly) missense change has a maximum subpopulation frequency of 0.027% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48033750-A-G). Five of seven in silico tools predict a damaging effect of this variant on protein function (PP3), but these predictions have not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer (PMID: 16940983, 18033691) and an individual with suspected Lynch syndrome (PMID: 25980754). It has also been reported in an individual with pancreatic ductal adenocarcinoma and family history of miscellaneous cancer types (PMID: 28767289). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 05, 2024	This missense variant replaces arginine with glycine at codon 1321 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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-associated cancer and/or polyps, pancreatic, kidney, uterine, omentum cancer, breast cancer, or glioblastoma (PMID: 16940983, 18033691, 25980754, 26648449, 26689913, 28767289, 29596542, 29684080, 31422818, 31391288, 33471991, 35264596; DOI: 10.1101/2021.04.15.21255554), including one case with a pathogenic MSH2 covariant (PMID: 25980754). In a large breast cancer case-control study, the variant was observed in 31/60466 cases and 37/53461 unaffected controls (PMID: 33471991). This variant has also been identified in 39/279718 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. -

Colorectal cancer, early onset

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

MSH6-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2024

The MSH6 c.3961A>G variant is predicted to result in the amino acid substitution p.Arg1321Gly. This variant has been reported in individuals with Lynch syndrome and sporadic, early-onset colorectal cancer (Barnetson et al. 2008. PubMed ID: 18033691; Pinto et al. 2006. PubMed ID: 16940983, Yurgelun et al. 2015. PubMed ID: 25980754). This variant was also found with a MSH2 deletion variant in a patient with colorectal cancer (Le et al. 2017. PubMed ID: 28596308). Another missense variant involving the same amino acid residue (p.Arg1321Ser) has been reported in at least one individual with endometrial cancer (Devlin et al. 2008. PubMed ID: 18269114). This variant is reported in 0.027% of alleles in individuals of European (Non-Finnish) 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/89490/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MSH6 p.Arg1321Gly variant was identified in 3 of 2112 proband chromosomes (frequency: 0.0014) from individuals or families with colorectal cancer and was not identified in 2676 control chromosomes from healthy individuals (Bameston 2008, Le 2017, Pinto 2006). The variant was also identified in the following databases: dbSNP (ID: rs41295278) as With Uncertain significance allele, ClinVar (classified as uncertain significance by InSight, Genedx, Ambry Genetics, Counsyl, Mayo Clinic; as likely benign by Invitae), Clinvitae (classified as uncertain significance by ClinVar), MutDB (classified as polymorphism), UMD-LSDB (3X neutral), Insight Colon Cancer Gene Variant Database (8X class3), Mismatch Repair Genes Variant Database, and the Insight Hereditary Tumors Database (9X). In UMD the variant was identified with a co-occurring pathogenic MSH6 variant (c.3514dup (p.Arg1172LysfsX5)), increasing the likelihood that the p.Arg1321Gly variant does not have clinical significance. The variant was not identified in the COGR, Cosmic, or Zhejiang Colon Cancer Databases. The variant was identified in control databases in 40 of 274126 chromosomes at a frequency of 0.0002 in the following populations: African in 1 of 23864 chromosomes (freq. 0.00004), other in 2 of 6418 chromosomes (freq. 0.0003), European in 35 of 124972 chromosomes (freq. 0.0003), increasing the likelihood that this may be a low frequency increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Arg1321 residue is conserved in mammals but not in more distantly related 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 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant is located with the DNA mismatch repair protein MutS, C-terminal P-loop containing nucleoside triphosphate hydrolase and DNA mismatch repair Msh6 functional domains. 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. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

.;.;T;D;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

.;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.26

T;T;T;T;T

MetaSVM

Uncertain

0.039

MutationAssessor

Benign

1.0

.;.;.;L;.

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.6

.;D;.;D;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.010

.;D;.;D;D

Sift4G

Uncertain

0.014

D;D;D;D;D

Polyphen

0.54

.;.;.;P;.

Vest4

0.59

MVP

0.89

ClinPred

0.12

GERP RS

6.0

Varity_R

0.65

gMVP

0.59

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