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

gnomAD frequency: 0.00001  dbSNP: rs587779340

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162757	SCV000213233	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-28	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000524468	SCV000261085	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing	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.
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
GeneDx	RCV000216802	SCV000279538	pathogenic	not provided	2022-06-10	criteria provided, single submitter	clinical testing	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)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000515494	SCV000611600	pathogenic	Lynch syndrome 4	2017-09-14	criteria provided, single submitter	research
Counsyl	RCV000515494	SCV000677814	likely pathogenic	Lynch syndrome 4	2017-02-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763591	SCV000894430	pathogenic	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255210	SCV000920018	pathogenic	Hereditary nonpolyposis colon cancer	2020-06-22	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000216802	SCV002047295	pathogenic	not provided	2020-11-16	criteria provided, single submitter	clinical testing	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149993	SCV003837739	pathogenic	Breast and/or ovarian cancer	2021-07-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000515494	SCV004019796	likely pathogenic	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000515494	SCV004207813	pathogenic	Lynch syndrome 4	2023-06-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162757	SCV004359698	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-31	criteria provided, single submitter	clinical testing	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.
All of Us Research Program, National Institutes of Health	RCV000205731	SCV004814295	pathogenic	Lynch syndrome	2024-01-22	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000216802	SCV000691979	pathogenic	not provided		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000216802	SCV001552740	pathogenic	not provided		no assertion criteria provided	clinical testing	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.