rs866260675
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePP3_StrongPP5_Very_Strong
The NM_002439.5(MSH3):c.2319-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000705 in 1,418,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_002439.5 splice_acceptor
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 |
---|---|---|---|---|---|---|---|
MSH3 | NM_002439.5 | c.2319-1G>A | splice_acceptor_variant | ENST00000265081.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH3 | ENST00000265081.7 | c.2319-1G>A | splice_acceptor_variant | 1 | NM_002439.5 | P2 | |||
MSH3 | ENST00000658259.1 | c.2151-1G>A | splice_acceptor_variant | A2 | |||||
MSH3 | ENST00000667069.1 | c.2124-1G>A | splice_acceptor_variant | ||||||
MSH3 | ENST00000670357.1 | c.2319-1G>A | splice_acceptor_variant, NMD_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000705 AC: 10AN: 1418538Hom.: 0 Cov.: 27 AF XY: 0.00000988 AC XY: 7AN XY: 708470
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 27, 2023 | Published functional studies demonstrate a damaging effect: in-frame loss of adjacent exon 17 (Adam et al., 2016); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 33193653, 34843512, 28875981, 34961301, 27476653) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | MSH3: PVS1, PM2, PM3, PS4:Moderate, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | This sequence change affects an acceptor splice site in intron 16 of the MSH3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with MSH3-associated polyposis (PMID: 27476653; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 253325). Studies have shown that disruption of this splice site results in skipping of exon 17, but is expected to preserve the integrity of the reading-frame (PMID: 27476653; Invitae). For these reasons, this variant has been classified as Pathogenic. - |
Familial adenomatous polyposis 4 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 31, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 30, 2023 | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 04, 2022 | The c.2319-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 17 of the MSH3 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant has been reported in the heterozygous state in studies of individuals with gastrointestinal cancers (Djursby M et al. Front Genet, 2020 Sep;11:566266; Vogelaar IP et al. Eur J Hum Genet, 2017 11;25:1246-1252). In another study, this variant was identified in conjunction with a MSH3 frameshift mutation in two siblings with multiple colorectal adenomatous polyps (one sibling was also diagnosed with astrocytoma, duodenal adenomas, thyroid adenomas, and intraductal papillomas). This patient had constitutional MSH3 loss on immunohistochemical staining. The same study found that c.2319-1G>A caused abnormal splicing resulting in the loss of exon 17, which is expected to cause an in-frame deletion of 39 amino acids at the protein level (Adam R et al. Am. J. Hum. Genet., 2016 Aug;99:337-51). Based on internal structural analysis, loss of exon 17 impacts the lever domain and is predicted to impair DNA binding (Gupta S et al. Nat. Struct. Mol. Biol., 2011 Dec;19:72-8; Ambry internal data). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Endometrial carcinoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 24, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at