rs386833406
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM1PM2PM5PP3_StrongBP6
The NM_000251.3(MSH2):c.2276G>A(p.Gly759Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. G759R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.2276G>A | p.Gly759Glu | missense_variant | 14/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.2276G>A | p.Gly759Glu | missense_variant | 14/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 27, 2019 | The p.G759E variant (also known as c.2276G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide position 2276. The glycine at codon 759 is replaced by glutamic acid, an amino acid with similar properties. This variant has been reported as an uncertain variant in the colorectal tumor specimen of one patient (van Puijenbroek M et al. Fam. Cancer, 2008 Apr;7:319-30). This variant has also been reported as a secondary finding in 6 out of 184 ClinSeq participants, unselected for personal or family history of cancer, who underwent exome sequencing; however, the clinical information for these particular individuals was not provided (Johnston JJ et al. Am. J. Hum. Genet., 2012 Jul;91:97-108). To examine functional significance of this alteration, one group used oligonucleotide-directed mutagenesis to examine MSH2 variants and found that p.G759E may have an intermediate pathogenic phenotype, as it conferred partial sensitivity to a DNA-damaging agent (6TG) but could only be detected only using a screening method that was optimized for the identification of partially pathogenic variants (Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A., 2016 Apr;113:4128-33). Using a cell-free assay to investigate MMR activity of MSH2 and MSH6 variants, another study found p.G759E to be missmatch repair deficient (Drost M et al. Hum. Mutat., 2012 Mar;33:488-94). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Lynch syndrome 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Benign:1
Benign, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at