ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1112_1113delinsTTTA (p.Asn371fs)

dbSNP: rs587779326
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076795 SCV000108277 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx RCV000115650 SCV000149559 pathogenic not provided 2023-04-05 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (gnomAD); Observed in a family with Lynch syndrome with variant allele showing no mRNA expression and an individual with breast cancer (Suerink et al., 2016; Susswein et al., 2016); This variant is associated with the following publications: (PMID: 26681312, 29345684, 32719484, 26110232)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115650 SCV000889605 pathogenic not provided 2017-12-20 criteria provided, single submitter clinical testing
Invitae RCV000813059 SCV000953396 pathogenic Hereditary nonpolyposis colorectal neoplasms 2023-11-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn371Ilefs*2) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with breast cancer and/or clinical features of Lynch syndrome (PMID: 26110232, 26681312). Studies have shown that this premature translational stop signal alters PMS2 gene expression (PMID: 26110232). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001017357 SCV001178430 pathogenic Hereditary cancer-predisposing syndrome 2022-10-05 criteria provided, single submitter clinical testing The c.1112_1113delATinsTTTA pathogenic mutation, located in coding exon 10 of the PMS2 gene, results from the deletion of two nucleotides and insertion of 4 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.N371Ifs*2). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med., 2016 08;18:823-32). This alteration has also been reported in a genotype-phenotype correlation study of cancer risk in PMS2 mutation carriers (Suerink M et al. Genet. Med., 2016 Apr;18:405-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health RCV001017357 SCV001351215 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing This variant is located in the PMS2 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193255 SCV001361983 pathogenic Hereditary nonpolyposis colon cancer 2019-10-23 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1112_1113delinsTTTA (p.Asn371IlefsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251318 control chromosomes (gnomAD). c.1112_1113delinsTTTA has been reported in the literature in a family affected with Lynch Syndrome (Suerink_2015) and in at least one individual with a history of breast cancer (Susswein_2016, Roberts_2018). These data indicate that the variant is likely to be associated with disease. In functional studies, no mRNA expression was seen from the mutated allele (Suerink_2015). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. The variant has also been classified by an expert panel (InSiGHT) as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc. RCV003452983 SCV004187719 pathogenic Lynch syndrome 4 2023-09-20 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics RCV003452983 SCV004207893 pathogenic Lynch syndrome 4 2022-07-02 criteria provided, single submitter clinical testing

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