NM_000251.3:c.-3G>C
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000251.3(MSH2):c.-3G>C variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0000257 in 1,592,618 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
Consequence
NM_000251.3 5_prime_UTR
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152254Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000188 AC: 4AN: 212752Hom.: 0 AF XY: 0.0000173 AC XY: 2AN XY: 115598
GnomAD4 exome AF: 0.0000160 AC: 23AN: 1440364Hom.: 0 Cov.: 31 AF XY: 0.0000154 AC XY: 11AN XY: 714588
GnomAD4 genome AF: 0.000118 AC: 18AN: 152254Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74388
ClinVar
Submissions by phenotype
not specified Uncertain:2
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Variant summary: MSH2 c.-3G>C is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 1.9e-05 in 212752 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-3G>C has been reported in the literature in individuals affected with Colorectal Cancer (Yurgelun_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variant(s) have been reported (MLH1 c.2070_2071insTT, p.I691Lfs), providing supporting evidence for a benign role (Yurgelun_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 127624). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Lynch syndrome Uncertain:2
The MSH2 c.-3G>C variant was not identified in the literature nor was it identified in the COGR, Cosmic, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or InSiGHT Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs587779960 as "With Uncertain significance allele") and ClinVar (5x as uncertain significance by GeneDx, Ambry Genetics, Counsyl, Color Genomics, and Integrated Genetics/Laboratory Corporation of America). The variant was identified in control databases in 8 of 238158 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 7 of 20486 chromosomes (freq: 0.0003) and Latino in 1 of 30410 chromosomes (freq: 0.00003); it was not observed in the Other, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.-3G>C variant is located in the kozak consensus sequence and typically a purine (adenine or guanine) is always observed at this position, increasing the likelihood this variant may have clinical significance. 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. -
This variant is located in the 5' untranslated region of the MSH2 gene. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 7/244138 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. -
Hereditary cancer-predisposing syndrome Uncertain:2
This variant is located in the 5' untranslated region of the MSH2 gene. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 7/244138 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. -
The c.-3G>C variant is located in the 5' untranslated region (5’ UTR) of the MSH2 gene. This variant results from a G to C substitution 3 bases upstream from the first translated codon. This nucleotide position is not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Lynch syndrome 1 Uncertain:1Benign: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: 27363726]. -
not provided Uncertain:1Benign:1
The MSH2 c.-3G>C variant has not been reported in individuals with an MSH2 related cancer. However, this variant has been described in the Exome Aggregation Consortium (ExAC) in publication (PMID: 26888055 (2016)). The frequency of this variant in the general population, 0.00028 (6/21394 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -
Nucleotide substitution has no predicted effect on splicing and is not conserved across species; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533) -
MSH2-related disorder Uncertain:1
The MSH2 c.-3G>C variant is located in the 5' untranslated region. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127624/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary nonpolyposis colorectal neoplasms Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at