ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1239dup (p.Asp414fs) (rs267608159)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000200079 SCV000253841 pathogenic Hereditary nonpolyposis colon cancer 2018-10-23 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 11 of the PMS2 mRNA (c.1239dupA), causing a frameshift at codon 414. This creates a premature translational stop signal (p.Asp414Argfs*44) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic. This particular variant has been reported in individuals undergoing testing for Lynch syndrome (PMID: 26437257) and with a second pathogenic PMS2 variant in individuals affected with constitutional mismatch repair deficiency-associated tumors (PMID: 20205264, 25691505). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000484340 SCV000568205 pathogenic not provided 2018-11-06 criteria provided, single submitter clinical testing This duplication of one nucleotide in PMS2 is denoted c.1239dupA at the cDNA level and p.Asp414ArgfsX44 (D414RfsX44) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GAAAAAAA[dupA]GACG. The duplication causes a frameshift which changes an Aspartic Acid to an Arginine at codon 414, and creates a premature stop codon at position 44 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.1239dupA has been observed in the compound heterozygous state with a nonsense variant in an individual with brain cancer and duodenal cancer diagnosed prior to age 18, consistent with autosomal recessive constitutional mismatch repair deficiency syndrome (Vaughn 2010). This variant was also observed in an individual with early-onset colon cancer and family history meeting Amsterdam Criteria I (Carneiro da Silva 2015). We consider this variant to be pathogenic.
Ambry Genetics RCV000562604 SCV000663437 pathogenic Hereditary cancer-predisposing syndrome 2017-07-13 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)
GeneKor MSA RCV000562604 SCV000821765 pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484340 SCV000889609 pathogenic not provided 2018-02-22 criteria provided, single submitter clinical testing
Color RCV000562604 SCV000906644 pathogenic Hereditary cancer-predisposing syndrome 2016-08-01 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000484340 SCV000691975 pathogenic not provided no assertion criteria provided clinical testing
Gharavi Laboratory,Columbia University RCV000484340 SCV000809469 pathogenic not provided 2018-09-16 no assertion criteria provided research

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