2-47806491-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000179.3(MSH6):c.3841G>C(p.Glu1281Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000179.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152094Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250892Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135698
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461804Hom.: 0 Cov.: 35 AF XY: 0.00000825 AC XY: 6AN XY: 727206
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152094Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74296
ClinVar
Submissions by phenotype
Lynch syndrome Uncertain:2
This missense variant replaces glutamic acid with glutamine at codon 1281 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 reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250892 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. -
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not provided Uncertain:2
The MSH6 p.Glu1281Gln variant was not identified in the literature nor was it identified in the COGR, COSMIC, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs876659115) as “With Uncertain significance allele”, and in the ClinVar and Clinvitae databases (classified as uncertain significance by Ambry Genetics and Color Genomics). The variant was identified in control databases in 1 of 245856 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was observed in the Latino population in 1 of 33540 chromosomes (freq: 0.00003), but not in the African, Other, European Non-Finnish, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Glu1281 residue is conserved across mammals and other organisms, and four out of five 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 1 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. 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. -
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an unaffected individual with a family history of breast and/or ovarian cancer (Lerner-Ellis et al., 2021); This variant is associated with the following publications: (PMID: 17531815, 21120944, 32885271) -
Hereditary cancer-predisposing syndrome Uncertain:2
The p.E1281Q variant (also known as c.3841G>C), located in coding exon 9 of the MSH6 gene, results from a G to C substitution at nucleotide position 3841. The glutamic acid at codon 1281 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
This missense variant replaces glutamic acid with glutamine at codon 1281 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250892 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. -
Endometrial carcinoma Uncertain:1
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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