2-47783226-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000179.3(MSH6):​c.-8C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000906 in 1,611,260 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000090 ( 1 hom. )

Consequence

MSH6
NM_000179.3 5_prime_UTR_premature_start_codon_gain

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:6

Conservation

PhyloP100: 1.07
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.73).
BP6
Variant 2-47783226-C-T is Benign according to our data. Variant chr2-47783226-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89164.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=5}.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000905 (132/1458930) while in subpopulation MID AF= 0.00191 (11/5764). AF 95% confidence interval is 0.00107. There are 1 homozygotes in gnomad4_exome. There are 73 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH6NM_000179.3 linkc.-8C>T 5_prime_UTR_premature_start_codon_gain_variant Exon 1 of 10 ENST00000234420.11 NP_000170.1 P52701-1Q3SWU9
MSH6NM_000179.3 linkc.-8C>T 5_prime_UTR_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 linkc.-8C>T 5_prime_UTR_premature_start_codon_gain_variant Exon 1 of 10 1 NM_000179.3 ENSP00000234420.5 P52701-1
MSH6ENST00000234420 linkc.-8C>T 5_prime_UTR_variant Exon 1 of 10 1 NM_000179.3 ENSP00000234420.5 P52701-1

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152222
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000119
AC:
29
AN:
244110
Hom.:
1
AF XY:
0.000105
AC XY:
14
AN XY:
133430
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000879
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000397
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.000100
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000905
AC:
132
AN:
1458930
Hom.:
1
Cov.:
30
AF XY:
0.000101
AC XY:
73
AN XY:
725866
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000897
Gnomad4 ASJ exome
AF:
0.0000384
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000372
Gnomad4 FIN exome
AF:
0.0000574
Gnomad4 NFE exome
AF:
0.0000594
Gnomad4 OTH exome
AF:
0.000249
GnomAD4 genome
AF:
0.0000919
AC:
14
AN:
152330
Hom.:
0
Cov.:
33
AF XY:
0.000107
AC XY:
8
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000580
Hom.:
0
Bravo
AF:
0.000106
EpiCase
AF:
0.000218
EpiControl
AF:
0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:4Benign:1
Feb 26, 2016
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 25, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: MSH6 c.-8C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 9.1e-05 in 1611260 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer (9.1e-05 vs 0.00014), allowing no conclusion about variant significance. c.-8C>T has been reported in the literature without strong evidence for or against pathogenicity (de Oliveira_2022). This report does 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: 26888055, 35534704). ClinVar contains an entry for this variant (Variation ID: 89164). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Oct 27, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Lynch syndrome 5 Uncertain:2Benign:1
Jul 05, 2016
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 08, 2023
Myriad Genetics, Inc.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely 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]. -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration results in substitution of nucleotide T for C in the 8 position upstream from codon one (5 prime untranslated region). This variant’s frequency is reported as T=0.00005 (6/115414, ExAC), T=0.000 (1/5008, 1000G), and T=0.0000 (1/30878, GnomAD). This variant is also reported in ClinVar as variant of unknown significance (10 reports). This variant is considered as variant of unknown significance. -

not provided Uncertain:2Benign:1
Jun 09, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Located in a region that tolerates variation and lacks pathogenic variants; This variant is associated with the following publications: (PMID: 26888055) -

Jan 28, 2018
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The MSH6 c.-8C>T variant (rs565211544) is not published in the medical literature, to our knowledge, but is listed as a variant of uncertain significance by several sources in the ClinVar database (Variation ID: 89164). The variant is listed in the Genome Aggregation Database in 30 out of 270614 alleles. This variant occurs 8 nucleotides before the translational start, the nucleotide at this position is not perfectly conserved across species, and the consequence of this substitution cannot be predicted with certainty. Studies of the transcriptional regulation of this region indicate this nucleotide may be involved in the regulation of this gene (Gazzoli 2003, Szadkowski 2002). Additionally, a translational prediction algorithm (NetStart 1.0) predicts this variant may alter translation. Considering available information, the clinical significance of this variant cannot be determined with certainty. References: Gazzoli I and Kolodner R. Regulation of the human MSH6 gene by the Sp1 transcription factor and alteration of promoter activity and expression by polymorphisms. Mol Cell Biol. 2003 Nov;23(22):7992-8007. Szadkowski M and Jiricny J. Identification and functional characterization of the promoter region of the human MSH6 gene. Genes Chromosomes Cancer. 2002 Jan;33(1):36-46. -

May 01, 2019
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Dec 09, 2021
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 31, 2013
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.-8C>T variant is located in the 5' untranslated region (5’ UTR) of the MSH6 gene. This variant results from a C to T substitution 8 nucleotides upstream from the first translated codon. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project.To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 12,000 alleles tested) in our clinical cohort (includes this individual).This nucleotide position is well conserved in available vertebrate species.Since supporting evidence for this variant is limited at this time, the clinical significance of this variant remains unclear. -

Endometrial carcinoma Uncertain:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The MSH6 c.-8C>T variant was not identified in literature nor the UMD-LSDB database. The variant was identified in dbSNP (ID: rs565211544) as "With other allele", ClinVar (classified as uncertain significance by Ambry Genetics, Counsyl, Quest Diagnostics, ARUP Laboratories, Mayo Clinic, Integrated Genetics, InSiGHT, University of Chicago; classified as benign by GeneDx). The variant was identified in control databases in 30 of 270614 chromosomes (1 homozygous) at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 3 of 34030 chromosomes (freq: 0.00009), European Non-Finnish in 11 of 122794 chromosomes (freq: 0.00009), European Finnish in 3 of 25752 chromosomes (freq: 0.0001), and South Asian in 13 of 30416 chromosomes (freq: 0.0004, increasing the likelihood this could be a low frequency benign variant), while the variant was not observed in the African, Other, Ashkenazi Jewish, or East Asian populations. This variant is located in the MSH6 promoter region, 8 nucleotides before the translational start. The nucleotide at this position is not perfectly conserved across species and the consequence of this substitution cannot be predicted with certainty. The MSH6 promoter region has a high GC content and consensus binding sequences for a number of transcription factors (Szadkowski 2002), suggesting variants in this region could affect expression. This variant was identified by our laboratory in the homozygous state in a patient with MSH6-deficient endometrial cancer but who does not have Constitutional Mismatch Repair Deficiency syndrome; however, we cannot rule out the possibility that this variant may result in reduced expression. 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. -

Lynch syndrome Benign:1
Jan 03, 2024
All of Us Research Program, National Institutes of Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

MSH6-related disorder Benign:1
Mar 08, 2020
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.73
CADD
Benign
15
DANN
Benign
0.88

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.

Other links and lift over

dbSNP: rs565211544; hg19: chr2-48010365; COSMIC: COSV52281564; COSMIC: COSV52281564; API