rs374840361
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PP3_ModerateBP6
The NM_000251.3(MSH2):c.1927G>A(p.Glu643Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.1927G>A | p.Glu643Lys | missense_variant | 12/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.1927G>A | p.Glu643Lys | missense_variant | 12/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151968Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251452Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135898
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461780Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11AN XY: 727194
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151968Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74218
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 19, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: increased mutation rate compared to wild type controls in a yeast based assay (Ollodart et al., 2020); Observed in individuals with a personal history of ovarian cancer or pancreatic ductal adenocarcinoma (Pal et al., 2012; Shindo et al., 2017; Hu et al., 2020); This variant is associated with the following publications: (PMID: 25637381, 23047549, 28767289, 32659497, 27535533, 18822302, 21120944, 33848333) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 17, 2022 | The frequency of this variant in the general population, 0.000035 (4/113736 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with ovarian cancer (PMID: 23047549 (2012)) and pancreatic cancer (PMID: 32659497 (2020), 28767289 (2017)). A yeast based functional study has reported inconclusive findings regarding the effect on this variant on MSH2 protein function (PMID: 33848333 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 09, 2021 | This missense variant replaces glutamic acid with lysine at codon 643 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). However, a functional study has reported that this variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). This variant has been reported in one individual each affected with ovarian cancer (PMID: 23047549) and pancreatic cancer (PMID: 28767289, 32659497). This variant has also been observed in trans with a pathogenic whole gene deletion of the MSH2 gene in an individual affected with an unspecified gynecological cancer (ClinVar variation ID 161299). This variant has been identified in 4/251452 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 03, 2023 | 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 12, 2022 | Variant summary: MSH2 c.1927G>A (p.Glu643Lys) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251452 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1927G>A has been reported in individuals affected with Ovarian Cancer and Pancreatic Cancer, however these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome (Pal_2012, Shindo_2017). One publication using the yeast ortholog of the variant showed a modest increase in random mutation rates in a continuous culture assay (Ollodart_2021). The increase in mutation rates observed did not indicate loss of function, therefore not allowing for convincing conclusions about the variant on protein function. Five ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
MSH2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 11, 2023 | The MSH2 c.1927G>A variant is predicted to result in the amino acid substitution p.Glu643Lys. This variant was reported in an individual with ovarian cancer and an individual with pancreatic adenocarcinoma (Table 2, Pal et al. 2012. PubMed ID: 23047549; Table A2, Shindo et al. 2017. PubMed ID: 28767289). This variant is reported in 4 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/2-47702331-G-A; Table S1, Amendola et al. 2015. PubMed ID: 25637381) and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/161299/643). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Ovarian cancer Uncertain:1
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Lynch syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 21, 2023 | - - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 28, 2023 | This missense variant replaces glutamic acid with lysine at codon 643 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). However, a functional study has reported that this variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). This variant has been reported in one individual each affected with ovarian cancer (PMID: 23047549) and pancreatic cancer (PMID: 28767289, 32659497). This variant has also been observed in trans with a pathogenic whole gene deletion of the MSH2 gene in an individual affected with an unspecified gynecological cancer (ClinVar variation ID 161299). This variant has been identified in 4/251452 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. - |
Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | - - |
Lynch syndrome;C5436806:Mismatch repair cancer syndrome 2 Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 04-20-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at