ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2117del (p.Lys706fs) (rs587782704)

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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 RCV000132155 SCV000187229 pathogenic Hereditary cancer-predisposing syndrome 2018-01-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000221406 SCV000279149 pathogenic not provided 2019-01-14 criteria provided, single submitter clinical testing This deletion of one nucleotide in PMS2 is denoted c.2117delA at the cDNA level and p.Lys706SerfsX19 (K706SfsX19) at the protein level. The normal sequence, with the base that is deleted in brackets, is GAGA[delA]GTAT. The deletion causes a frameshift, which changes a Lysine to a Serine at codon 706, and creates a premature stop codon at position 19 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. PMS2 c.2117delA has been reported in the heterozygous state in individuals with microsatellite-unstable colorectal cancer as well as in multiple members of a family with Lynch syndrome (Goodenberger 2015, Suerink 2015, Yurgelun 2017). Additionally, this variant has been reported in the homozygous or compound heterozygous state in individuals with constitutional mismatch repair deficiency (Adam 2016, Bouffet 2016). We consider this deletion to be pathogenic.
Invitae RCV000524458 SCV000285105 pathogenic Hereditary nonpolyposis colon cancer 2019-01-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys706Serfs*19) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases (rs587782704, ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been reported in individuals affected with Lynch syndrome (PMID: 26110232, 23012243, 25856668, 28135145), constitutional mismatch repair deficiency syndrome (CMMR-D) (PMID: 27001570, 27476653), and ovarian cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 142765). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000228992 SCV000592945 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506059 SCV000604886 pathogenic not specified 2016-08-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000228992 SCV000697329 pathogenic Lynch syndrome 2016-12-15 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.2117delA (p.Lys706Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.2186_2187delTC/p.Leu729fs). One in silico tool predicts a damaging outcome for this variant. This variant has been reported in one CRC patient in heterozygous state, 2 patients with glioblastoma multiforme in homozygous state, and one patient with constitutional MMR deficiency in compound heterozygous state (c.1A>T [likely pathogenic] in trans). This variant is absent in 98900 control chromosomes. However, it was found in one 64 y.o. patient without cancer in heterozygous state, indicating this variant has low penetrance. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000228992 SCV000712647 pathogenic Lynch syndrome 2016-11-25 criteria provided, single submitter clinical testing The p.Lys706fs variant in PMS2 has been reported in the heterozygous state in tw o individuals with colorectal cancer and one unaffected individual (Vaughn 2013, Goodenberger 2015), as well as in 4 individuals from a family included in a stu dy of presymptomatic and symptomatic variant carriers (Suerink 2015, no clinical details provided). It has been reported in the homozygous state in two sibling s with constitutional mismatch repair deficiency syndrome (Bouffet 2016). This v ariant was absent from large population studies, though the ability of these stu dies to accurately detect indels may be limited. This variant is predicted to ca use a frameshift, which alters the protein?s amino acid sequence beginning at po sition 706 and leads to a premature termination codon 19 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein, whi ch was confirmed experimentally (Suerink 2015, data not shown). Heterozygous los s of function of function of the PMS2 gene is an established disease mechanism i n Lynch Syndrome. In summary, the p.Lys706fs meets our criteria to be classified as pathogenic.
PreventionGenetics,PreventionGenetics RCV000221406 SCV000806152 pathogenic not provided 2016-11-02 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000709753 SCV000840045 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2017-09-19 criteria provided, single submitter clinical testing The c.2117delA (p.Lys706Serfs*19) variant has been in a 53 y/o female with colorectal cancer in the transverse colon [PMID 5856668], an also detected in a family with Lynch syndrome [PMID 26110232]. This variant was also recently detected at the homozygous state in 2 young siblings with recurrent gliobalstoma multiforme and NF1 features [PMID 27001570]. Treatment with the anti-programmed death-1 inhibitor nivolumab resulted in clinically significant responses and a profound radiologic response. This variant was not observed in the ExAC population database nor in our patient cohort. This 1 bp deletion is located in exon 12, and leads to a frameshift and a premature stop codon. This variant is expected to result in a loss of function of the protein and is thus classified as pathogenic. Pathogenic variant in the PMS2 gene are considered medically actionable [ACMG59, PMID 27854360]
GenomeConnect, ClinGen RCV000509483 SCV000607287 not provided Hereditary cancer no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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