ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1970dup (p.Asn657fs) (rs1064794566)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485653 SCV000569465 pathogenic not provided 2016-03-22 criteria provided, single submitter clinical testing This duplication of one nucleotide in PMS2 is denoted c.1970dupA at the cDNA level and p.Asn657LysfsX7 (N657KfsX7) at the protein level. The normal sequence, with the base that is duplicated in braces, is GAAA[A]TCAA. The duplication causes a frameshift which changes an Asparagine to a Lysine at codon 657, and creates a premature stop codon at position 7 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.1970dupA has been reported in an individual with a cecal cancer demonstrating loss of PMS2 protein and another individual with a personal/family history suspicious for Lynch syndrome (Goldberg 2014, Goodenberger 2016). We consider this variant to be pathogenic.
Invitae RCV000541652 SCV000625570 pathogenic Hereditary nonpolyposis colon cancer 2019-11-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn657Lysfs*7) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family affected with Lynch syndrome, and has been described as a common variant in the Iranian Jewish population (PMID: 25430799). ClinVar contains an entry for this variant (Variation ID: 420579). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001013897 SCV001174537 pathogenic Hereditary cancer-predisposing syndrome 2018-03-14 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)

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