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
Consequence
NM_000179.3 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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MSH6 | NM_000179.3 | c.-8C>T | 5_prime_UTR_premature_start_codon_gain_variant | Exon 1 of 10 | ENST00000234420.11 | NP_000170.1 | ||
MSH6 | NM_000179.3 | c.-8C>T | 5_prime_UTR_variant | Exon 1 of 10 | ENST00000234420.11 | NP_000170.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420 | c.-8C>T | 5_prime_UTR_premature_start_codon_gain_variant | Exon 1 of 10 | 1 | NM_000179.3 | ENSP00000234420.5 | |||
MSH6 | ENST00000234420 | c.-8C>T | 5_prime_UTR_variant | Exon 1 of 10 | 1 | NM_000179.3 | ENSP00000234420.5 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000119 AC: 29AN: 244110Hom.: 1 AF XY: 0.000105 AC XY: 14AN XY: 133430
GnomAD4 exome AF: 0.0000905 AC: 132AN: 1458930Hom.: 1 Cov.: 30 AF XY: 0.000101 AC XY: 73AN XY: 725866
GnomAD4 genome AF: 0.0000919 AC: 14AN: 152330Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74482
ClinVar
Submissions by phenotype
not specified Uncertain:4Benign:1
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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. -
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Lynch syndrome 5 Uncertain:2Benign:1
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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]. -
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
Located in a region that tolerates variation and lacks pathogenic variants; This variant is associated with the following publications: (PMID: 26888055) -
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. -
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Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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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
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
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MSH6-related disorder Benign:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at