chr2-47480795-A-C
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_000251.3(MSH2):c.2558A>C(p.Glu853Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,614,030 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. E853G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.2558A>C | p.Glu853Ala | missense_variant | 15/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.2558A>C | p.Glu853Ala | missense_variant | 15/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251450Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135896
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461820Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727210
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74350
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 06, 2023 | - - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 09, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 21, 2022 | 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 provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 15, 2023 | 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 suggest a neutral effect: restored mismatch repair (MMR) function in a MSH2 knockout cell line (Jia et al., 2020); Not observed in any cases, but was observed in unaffected controls from a colorectal cancer/polyposis study (Rosenthal et al., 2018); Observed in individuals with suspected Lynch syndrome; however, the variant did not co-segregate with the disease in the family (Kurzawski et al., 2002); This variant is associated with the following publications: (PMID: 26333163, 16451135, 18383312, 11879922, 18822302, 21120944, 33357406, 12362047, 30267214) - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 02, 2018 | - - |
Lynch syndrome 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 01, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 06, 2023 | This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. - |
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Carcinoma of colon Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH2 p.Glu853Ala variant was identified in 3 of 450 proband chromosomes (frequency: 0.006) from individuals or families with colorectal cancer or Lynch syndrome-associated cancer from Poland (Kurzawski 2002, Kurzawski 2006, Kurzawski 2002). The variant was also identified in dbSNP (ID: rs63750797) as “With Uncertain significance allele”, ClinVar (classified as uncertain significance by InSiGHT, Ambry Genetics, GeneDx, Invitae, Color, Counsyl, Prevention Genetics, and Mayo Clinic). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 5 of 277226 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24040 chromosomes (freq: 0.00004) and European in 4 of 126708 chromosomes (freq: 0.00003); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish or South Asian populations. The p.Glu853 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. - |
Lynch syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Mar 23, 2023 | This missense variant replaces glutamic acid with alanine at codon 853 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in a family affected with hereditary non-polyposis colorectal cancer, who also carried a pathogenic variant in the same gene (PMID: 11879922, 12362047, 16451135). It was reported that this variant did not segregate with disease in this family (PMID: 12362047). This variant has been identified in 4/282858 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
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at