chr2-47414279-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP3BP6
The NM_000251.3(MSH2):c.803C>T(p.Ser268Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,460 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S268A) has been classified as Likely benign.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.803C>T | p.Ser268Leu | missense_variant | 5/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.803C>T | p.Ser268Leu | missense_variant | 5/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151926Hom.: 0 Cov.: 29
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251012Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135674
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461416Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727006
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152044Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 74330
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 07, 2023 | In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 31569399 (2019), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). One functional study utilizing a minigene assay suggested that this variant may cause exon skipping (PMID: 32741062 (2020)), but additional studies are needed to determine the global impact of this variant on gene and gene product. The frequency of this variant in the general population, 0.000008 (2/251012 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH2 p.Ser268Leu variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors database. The variant was identified in dbSNP (ID: rs563410947) as "With Uncertain significance allele”, and in ClinVar database (classified as uncertain significance by Invitae). The variant was identified in control databases in 2 of 245922 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 2 of 30674 chromosomes (freq: 0.000065), but not in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Ser268 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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) 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 | Feb 11, 2020 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 20, 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 30, 2021 | This missense variant replaces serine with leucine at codon 268 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251012 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. - |
Lynch syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 23, 2023 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at