2-47791123-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000179.3(MSH6):c.457G>A(p.Gly153Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G153C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000179.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.457G>A | p.Gly153Ser | missense_variant, splice_region_variant | 2/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.457G>A | p.Gly153Ser | missense_variant, splice_region_variant | 2/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 19, 2023 | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 2 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 410411). This missense change has been observed in individuals with clinical features of Lynch syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 153 of the MSH6 protein (p.Gly153Ser). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 25, 2022 | The p.G153S pathogenic mutation (also known as c.457G>A), located in coding exon 2 of the MSH6 gene, results from a G to A substitution at nucleotide position 457. The amino acid change results in glycine to serine at codon 153, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. This variant has been identified in probands with Lynch syndrome-associated tumors that demonstrated high microsatellite instability and loss of MSH6 expression by immunohistochemistry (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is interpreted as a disease-causing mutation. - |
Endometrial carcinoma Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH6 p.Gly153Ser variant was not identified in the literature nor was it identified in the dbSNP, GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was identified in ClinVar (1x as uncertain significance by Invitae), Clinvitae (1x as uncertain significance by Invitae), databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Gly153 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 p.Gly153Ser variant occurs in the last three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at