chr2-47416420-T-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000251.3(MSH2):c.1067T>G(p.Ile356Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Carcinoma of colon Pathogenic:1
The p.Ile356Arg variant was not identified in affected individuals in the literature. The variant was not identified in any databases searched (dbSNP, ClinVar, Clinvitae, COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), GeneInsight - COGR database, UMD, Exome Aggregation Consortium (ExAC) database, NHLBI GO Exome Sequencing Project (ESP)). A different variant at this position was identified in UMD in five samples as a causal variant (c.1067T>A, p.Ile356Lys), suggesting that this residue may play an important role in protein function. The variant was assessed in one study using an alignment-based algorithm, which predicted the variant to be pathogenic (Drost 2013). The p.Ile356 residue is conserved across mammals, and 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the potential creation of a cryptic splice acceptor site; this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although this variant meets our laboratory’s criteria to be classified as likely pathogenic. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 356 of the MSH2 protein (p.Ile356Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with constitutional mismatch repair deficiency syndrome (PMID: 30608896). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 433880). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 333574060) indicates that this missense variant is expected to disrupt MSH2 function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.I356R pathogenic mutation (also known as c.1067T>G), located in coding exon 6 of the MSH2 gene, results from a T to G substitution at nucleotide position 1067. The isoleucine at codon 356 is replaced by arginine, an amino acid with similar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). Based on internal structural analysis, this variant is buried in the MutS III domain of MSH2 and is highly destabilizing to the local structure (Ambry internal data). Another alteration at the same codon, p.I356K (c.1067T>A), has been detected in a proband diagnosed in her 50s with breast cancer as well as endometrial cancer that demonstrated loss of both MSH2/MSH6 expression by immunohistochemistry and the variant segregated with disease in a first degree relative with colorectal cancer (Fokkema IF et al. Hum Mutat, 2011 May;32:557-63), and was also determined to be functionally deleterious in a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG) (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at