NM_000179.3:c.98G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000179.3(MSH6):​c.98G>C​(p.Arg33Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,609,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R33G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: -1.08

Publications

4 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 Gene-Disease associations (from GenCC):
  • Lynch syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
  • Lynch syndrome 5
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
  • mismatch repair cancer syndrome 1
    Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • mismatch repair cancer syndrome 3
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
  • ovarian cancer
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • malignant pancreatic neoplasm
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • Muir-Torre syndrome
    Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
  • rhabdomyosarcoma
    Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
  • breast cancer
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • prostate cancer
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • hereditary breast carcinoma
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 16 uncertain in NM_000179.3
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.09068298).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH6NM_000179.3 linkc.98G>C p.Arg33Pro missense_variant Exon 1 of 10 ENST00000234420.11 NP_000170.1 P52701-1Q3SWU9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MSH6ENST00000234420.11 linkc.98G>C p.Arg33Pro missense_variant Exon 1 of 10 1 NM_000179.3 ENSP00000234420.5 P52701-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152164
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1457610
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
725036
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33292
American (AMR)
AF:
0.0000224
AC:
1
AN:
44554
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26052
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39594
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86006
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51702
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5756
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1110496
Other (OTH)
AF:
0.00
AC:
0
AN:
60158
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.550
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152164
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74324
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41456
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5166
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4838
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68010
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2
Nov 21, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.R33P variant (also known as c.98G>C), located in coding exon 1 of the MSH6 gene, results from a G to C substitution at nucleotide position 98. The arginine at codon 33 is replaced by proline, an amino acid with dissimilar properties. This alteration has been reported in a 30-year-old individual diagnosed with microsatellite stable colorectal cancer who had no reported family history of cancer (Perez-Cabornero L et al. J Mol Diagn. 2013 May;15(3):380-90). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Sep 20, 2023
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces arginine with proline at codon 33 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 reported for this variant. This variant has been reported in an individual with early-onset colorectal cancer with no other cancer history in the family (PMID: 23523604). The proband's tumor showed microsatellite stability. This variant has not been identified 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. -

MSH6-related disorder Uncertain:1
Jan 30, 2023
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The MSH6 c.98G>C variant is predicted to result in the amino acid substitution p.Arg33Pro. This variant was reported in at least one individual with colorectal cancer (Pérez-Cabornero et al. 2013. PubMed ID: 23523604). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is reported as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/237219/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Lynch syndrome Uncertain:1
Oct 06, 2023
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 proline at codon 33 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 reported for this variant. This variant has been reported in an individual with early-onset colorectal cancer with no other cancer history in the family (PMID: 23523604). The proband's tumor showed microsatellite stability. This variant has not been identified 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 Uncertain:1
May 02, 2016
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is denoted MSH6 c.98G>C at the cDNA level, p.Arg33Pro (R33P) at the protein level, and results in the change of an Arginine to a Proline (CGT>CCT). This variant was observed in at least one individual with early-onset colorectal cancer whose tumor was microsatellite stable (Pérez-Cabornero 2013). MSH6 Arg33Pro was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg33Pro occurs at a position that is not conserved and is not located in a known functional domain (Terui 2013). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Arg33Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Aug 13, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 33 of the MSH6 protein (p.Arg33Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 23523604). ClinVar contains an entry for this variant (Variation ID: 237219). 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) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Endometrial carcinoma Uncertain:1
Aug 20, 2023
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Lynch syndrome 5 Benign:1
Apr 29, 2024
Myriad Genetics, Inc.
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.072
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
10
DANN
Benign
0.79
DEOGEN2
Benign
0.24
.;T;T
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.0088
N
LIST_S2
Benign
0.72
T;T;T
M_CAP
Uncertain
0.19
D
MetaRNN
Benign
0.091
T;T;T
MetaSVM
Benign
-0.67
T
MutationAssessor
Benign
0.0
N;N;.
PhyloP100
-1.1
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
1.1
N;N;.
REVEL
Benign
0.19
Sift
Benign
0.16
T;T;.
Sift4G
Benign
0.26
T;T;T
Polyphen
0.0060
.;B;.
Vest4
0.11
MutPred
0.34
Loss of MoRF binding (P = 5e-04);Loss of MoRF binding (P = 5e-04);Loss of MoRF binding (P = 5e-04);
MVP
0.58
ClinPred
0.058
T
GERP RS
1.1
PromoterAI
0.037
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.15
gMVP
0.46
Mutation Taster
=95/5
polymorphism

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

Other links and lift over

dbSNP: rs878853751; hg19: chr2-48010470; API