ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.251-2A>T (rs587779340)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162757 SCV000213233 pathogenic Hereditary cancer-predisposing syndrome 2017-11-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Counsyl RCV000515494 SCV000677814 likely pathogenic Hereditary nonpolyposis colorectal cancer type 4 2017-02-16 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763591 SCV000894430 pathogenic Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000216802 SCV000279538 pathogenic not provided 2017-11-13 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.251-2A>T or IVS3-2A>T and consists of an A>T nucleotide substitution at the -2 position of intron 3 of the PMS2 gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been observed in an individual diagnosed with a Lynch syndrome-associated cancer and/or polyps and also in at least one individual with sarcoma and a family history of cancer (Yurgelun 2015, Shirts 2016). Based on the currently available information, we consider PMS2 c.251-2A>T to be a pathogenic variant.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000515494 SCV000611600 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2017-09-14 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000205731 SCV000920018 pathogenic Lynch syndrome 2018-01-15 criteria provided, single submitter clinical testing Variant summary: The c.251-2A>T (aka IVS3-2A>T) in a PMS2 gene is a splice-site variant that alters a highly conserved nucleotide. 5/5 in silico tools via Alamut predict this variant to disrupt a canonical donor sequence although no experimental confirmation of these predictions were published at the time of evaluation. The variant is present in control dataset of gnomAD at a low frequency of 0.000004 (1/ 239164 chrs tested). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.00011. The variant has been reported in affected individuals with confirmed dx of LS via publications and is cited as Pathogenic/Likely Pathogenic by a reputable database/clinical laboratories. In addition, other alteration of the same position, such as c.251-2A>G and c.251-2A>C, have been reported in multiple patients with LS. Taken together, the variant was classified as Pathogenic.
Invitae RCV000524468 SCV000261085 pathogenic Hereditary nonpolyposis colon cancer 2018-12-24 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 3 of the PMS2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (ExAC 0.002%). This variant has been reported in an individual affected with suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 183893). A different variant affecting this nucleotide (c.251-2A>G) has been determined to be pathogenic and reported on the opposite chromosome (in trans) from a pathogenic variant in two siblings with clinical features consistent with constitutional mismatch repair deficiency syndrome (PMID: 18602922, 21376568). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000205731 SCV000967786 pathogenic Lynch syndrome 2018-03-09 criteria provided, single submitter clinical testing 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000216802 SCV000691979 pathogenic not provided no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000205731 SCV000266117 likely pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing

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