rs267608016
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM5BP4_Moderate
The NM_000251.3(MSH2):c.2517T>A(p.His839Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. H839R) has been classified as Pathogenic.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.2517T>A | p.His839Gln | missense_variant | 15/16 | ENST00000233146.7 | NP_000242.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.2517T>A | p.His839Gln | missense_variant | 15/16 | 1 | NM_000251.3 | ENSP00000233146.2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152190Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251444Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135904
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461834Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727212
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152190Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74356
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 11, 2022 | This missense variant replaces histidine with glutamine at codon 839 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 colorectal cancer (PMID: 18383312) and an individual with a Lynch syndrome associated cancer (PMID: 18561205). This variant has been identified in 5/282852 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 02, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 28, 2019 | 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 | Sep 02, 2023 | - - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 10, 2023 | This missense variant replaces histidine with glutamine at codon 839 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 colorectal cancer (PMID: 18383312) and an individual with a Lynch syndrome associated cancer (PMID: 18561205). This variant has been identified in 5/282852 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 03, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with personal or family history suggestive of Lynch syndrome (Chao et al., 2008; Tournier et al., 2008); This variant is associated with the following publications: (PMID: 18561205, 18383312, 26333163, 30798936, 18822302, 21120944) - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH2 p.His839Gln variant was identified in 1 of 28 proband chromosomes (frequency: 0.04) from individuals or families with Lynch syndrome and was absent from 200 control chromosomes; however, the variant was also identified in 5 of 6 of the proband’s healthy relatives (Yuan 2004). The variant was identified in dbSNP (ID: rs267608016 as "With Uncertain significance allele"), ClinVar (1x as likely benign by Ambry Genetics and 3x as uncertain significance by InSight, Invitae, and GeneDx), UMD-LSDB (1x as unclassified variant), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database (9x as class 3). The variant was not identified in COGR, Cosmic, MutDB, or the Zhejiang University Database. The variant was identified in control databases in 5 of 277214 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 5 of 126712 chromosomes (freq: 0.00004), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.His839 residue is conserved in mammals but not in more distantly related organisms and 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence, however 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this information is not predictive enough to assume pathogenicity. Further, functional analysis using the pCAS ex vivo splicing assay demonstrated this variant had no effect on splicing (Tournier 2008). 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. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 24, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at