rs587779340
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PP3_StrongPP5_Very_Strong
The NM_000535.7(PMS2):c.251-2A>T variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000442 in 1,582,534 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_000535.7 splice_acceptor
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.251-2A>T | splice_acceptor_variant | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.251-2A>T | splice_acceptor_variant | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000409 AC: 1AN: 244282Hom.: 0 AF XY: 0.00000751 AC XY: 1AN XY: 133182
GnomAD4 exome AF: 0.00000419 AC: 6AN: 1430400Hom.: 0 Cov.: 26 AF XY: 0.00000701 AC XY: 5AN XY: 713756
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74308
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 16, 2020 | This variant is located in a canonical splice-acceptor site and interferes with normal PMS2 mRNA splicing. The variant has been reported in individuals with suspected Lynch syndrome in the published literature (PMID: 31992580 (2020), 25980754 (2015)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 10, 2022 | Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Yurgelun 2015, Wang 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25980754, 27779110, 26845104, 29625052, 31992580, 31447099, 32719484, 18602922) - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PMS2 c.251-2A>T variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch syndrome (Yurgelun 2015). The variant was also identified in dbSNP (ID: rs587779340) as "With Likely pathogenic, Pathogenic allele", ClinVar (classified as pathogenic by Ambry genetics, Invitae, GeneDx and two clinical laboratories; as likely benign by two submitters), and in Insight Hereditary Tumors Database (3x ). The variant was not identified in GeneInsight-COGR, Cosmic, or Mismatch Repair Genes Variant, databases. The variant was identified in control databases in 1 of 239164 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 108456 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The c.251-2A>T variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. A different variant affecting this nucleotide (c.251-2A>G) classified as pathogenic, has been found in Lynch syndrome patients as biallelic PMS2 gene mutation (Herkert 2011, Senter 2008). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Lynch syndrome 4 Pathogenic:4
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Sep 14, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 07, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 16, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 04, 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. - |
Lynch syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 09, 2018 | The c.251-2A>T variant in PMS2 has been reported in one individual with suspecte d Lynch syndrome (Yurgelun 2015) and has also been reported by other clinical la boratories in ClinVar (Variation ID# 183893). Additionally, two other variants a t this position (c.251-2A>C, c.251A>G) have been reported in individuals with PM S2-related cancers (Herkert 2011, Senter 2008), one of which has also been class ified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000108354.2). The c.251A>T variant has also been identified in 1/108456 European chromosomes by the Genome Aggregation Database (gnomAD, http: //gnomad.broadinstitute.org; dbSNP rs587779340). This frequency is low enough to be consistent with the frequency of Lynch syndrome in the general population. T his variant occurs in the invariant region (+/- 1,2) of the splice consensus seq uence and is predicted to cause altered splicing leading to an abnormal or absen t protein. Heterozygous loss of function of the PMS2 gene is an established dise ase mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal domi nant manner based upon predicted impact to the protein, very low frequency in th e general population and the presence of a different pathogenic variant at the s ame position. ACMG/AMP criteria applied (Richards 2015): PVS1, PM5, PM2. - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 22, 2024 | This variant causes an A to T nucleotide substitution at the -2 position of intron 3 of the PMS2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals suspected of having Lynch syndrome or colorectal cancer with clinical features of Lynch syndrome (PMID: 25980754, 31992580), in individuals with ovarian cancer (PMID: 33881185) and oligodendroglioma (PMID: 35982947). This variant has been identified in 1/244282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice donor site, c..251-2A>G and c.251-2A>C, are known to be disease-causing (ClinVar variation ID: 91345, 233781). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 31, 2023 | This variant causes an A to T nucleotide substitution at the -2 position of intron 3 of the PMS2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals suspected of having Lynch syndrome or colorectal cancer with clinical features of Lynch syndrome (PMID: 25980754, 31992580), in individuals with ovarian cancer (PMID: 33881185) and oligodendroglioma (PMID: 35982947). This variant has been identified in 1/244282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice donor site (c..251-2A>G, c.251-2A>C) are known to be disease-causing (ClinVar variation ID: 91345, 233781). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 28, 2022 | The c.251-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides before coding exon 4 in the PMS2 gene. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). This alteration has also been identified in an individual diagnosed with colorectal cancer at 54. Immunohistochemistry of the tumor showed loss of expression of MSH6 and PMS2 (Wang Q et al. J Med Genet, 2020 07;57:487-499). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Two other alterations at this position (c.251-2A>G and c.251-2A>C) have been reported as pathogenic in Lynch syndrome and CMMR-D cohorts (Senter L et al. Gastroenterology. 2008 Aug;135:419-28; Niessen RC et al. Genes Chromosomes Cancer. 2009 Apr;48:322-9). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. - |
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 28, 2021 | - - |
Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Hereditary nonpolyposis colon cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 22, 2020 | Variant summary: PMS2 c.251-2A>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 244282 control chromosomes (gnomAD). c.251-2A>T has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Yurgelun_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change affects an acceptor splice site in intron 3 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587779340, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with constitutional mismatch repair deficiency syndrome and/or Lynch syndrome (PMID: 18602922, 21376568, 25980754). ClinVar contains an entry for this variant (Variation ID: 183893). Studies have shown that disruption of this splice site results in skipping of exon 4 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at