rs587779970
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM5BP6
The ENST00000233146.7(MSH2):āc.328A>Cā(p.Lys110Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,458,316 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K110E) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000233146.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.328A>C | p.Lys110Gln | missense_variant | 2/16 | ENST00000233146.7 | NP_000242.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.328A>C | p.Lys110Gln | missense_variant | 2/16 | 1 | NM_000251.3 | ENSP00000233146 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251294Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135814
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1458316Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 725698
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 18, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 23, 2020 | Variant summary: MSH2 c.328A>C (p.Lys110Gln) results in a conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain (IPR007695) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251294 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.328A>C has been reported in the literature in an individual affected with colon and rectal cancer (deRosa_2016). This report however, 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. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH2 p.Lys110Gln variant was identified in 1 of 124 proband chromosomes (frequency: 0.008) from individuals or families with colon and rectal cancer (de Rosa 2016). The variant was also identified in the following databases: dbSNP (ID: rs587779970) as "With Uncertain significance allele ", ClinVar (3x uncertain significance), Clinvitae (2x uncertain significance), and the Cosmic database. The variant was not identified in MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 1 of 246102 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European in 1 of 111630 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Lys110 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the glutamine 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 16, 2019 | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with colorectal cancer (de Rosa 2016); This variant is associated with the following publications: (PMID: 25186949, 27432916, 22229248) - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 31, 2023 | This missense variant replaces lysine with glutamine at codon 110 of the MSH2 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). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with early-onset, mismatch repair deficient colorectal cancer (PMID: 27432916). This variant has also been identified in 1/251294 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 16, 2024 | 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. - |
Lynch syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 13, 2024 | - - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | This missense variant replaces lysine with glutamine at codon 110 of the MSH2 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). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with early-onset, mismatch repair deficient colorectal cancer (PMID: 27432916). This variant has also been identified in 1/251294 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 nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at