rs140754514
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000251.3(MSH2):āc.2537A>Gā(p.Gln846Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q846Q) has been classified as Likely benign.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.2537A>G | p.Gln846Arg | missense_variant | 15/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.2537A>G | p.Gln846Arg | missense_variant | 15/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000131 AC: 20AN: 152248Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251440Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135896
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461830Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727212
GnomAD4 genome ? AF: 0.000131 AC: 20AN: 152248Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9AN XY: 74394
ClinVar
Submissions by phenotype
not specified Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 20, 2017 | The p.Gln846Arg variant in MSH2 has not been previously reported in individuals with colorectal cancer. This variant has been identified in 3/10406 African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs140754514). Computational prediction tools and conservation analysis suggest that the p.Gln846Arg variant may not impact the protein, though this inf ormation is not predictive enough to rule out pathogenicity. In summary, the cli nical significance of the p.Gln846Arg variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 31, 2023 | Variant summary: MSH2 c.2537A>G (p.Gln846Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251440 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (5.6e-05 vs 0.00057), allowing no conclusion about variant significance. c.2537A>G has been reported in the literature in individuals affected with cancer, without strong evidence for causality (Gordon_2019, Li_2020). These report(s) do 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: 31422818, 31391288). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments: five classified as VUS while three classified as likely benign/benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Lynch syndrome 1 Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 13, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 20, 2023 | 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]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 11, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 06, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 06, 2019 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 12, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 10, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at