Submissions for variant NM_000535.7(PMS2):c.1021del (p.Arg341fs)

dbSNP: rs63750049

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076793	SCV000108275	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000076793	SCV000271437	pathogenic	Lynch syndrome	2019-04-19	criteria provided, single submitter	clinical testing	The p.Arg341GlyfsX15 variant in PMS2 has been identified in at least 1 individual with PMS2-associated cancer and segregated with the disease in 2 affected family members (one with endometrial cancer and one with colon polyps; Worthley 2005). This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 341 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of function of the PMS2 gene is an established disease mechanism in Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon predicted impact to the protein. ACMG/AMP Criteria applied: PM2, PVS1.
GeneDx	RCV000220282	SCV000279562	pathogenic	not provided	2018-09-04	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in PMS2 is denoted c.1021delA at the cDNA level and p.Arg341GlyfsX15 (R341GfsX15) at the protein level. The normal sequence, with the base that is deleted in brackets, is TAAA[delA]GGCA. The deletion causes a frameshift, which changes an Arginine to a Glycine at codon 341, and creates a premature stop codon at position 15 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.1021delA has been identified in a family meeting Amsterdam II criteria for HNPCC, and tumors from carriers of this variant have exhibited microsatellite instability and loss of PMS2 expression by immunohistochemistry (IHC) (Worthley 2005, Senter 2008). We consider this variant to be pathogenic.
Invitae	RCV000530149	SCV000625497	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 9240). This variant is also known as c.1018delA. This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15887099, 15887124, 18602922). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg341Glyfs*15) 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).
Ambry Genetics	RCV000570955	SCV000670738	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-30	criteria provided, single submitter	clinical testing	The c.1021delA pathogenic mutation, located in coding exon 10 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 1021, causing a translational frameshift with a predicted alternate stop codon (p.R341Gfs*15). This mutation has been reported in multiple individuals with early onset colon cancer and was found to segregate with disease in a family meeting Amsterdam II criteria (Worthley DL et al. Gastroenterology. 2005 May;128:1431-6; Senter L et al. Gastroenterology. 2008 Aug;135:419-28). This mutation was also detected in an individual with a history of prostate cancer at age 55 and colorectal cancer of the splenic flexure at 57. The authors referred to this alteration as c.1018delA (Truninger K et al. Gastroenterology. 2005 May;128:1160-71). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000570955	SCV000686090	pathogenic	Hereditary cancer-predisposing syndrome	2020-05-28	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with colorectal cancer (PMID: 15887124, 18602922) and sebaceous neoplasms (PMID: 29333623). 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	RCV001375488	SCV000697276	pathogenic	Hereditary nonpolyposis colon cancer	2021-04-08	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1021delA (p.Arg341GlyfsX15) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250990 control chromosomes (gnomAD). c.1021delA has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer and was shown to segregate with disease in at least 1 family (e.g. Truninger_2005, Worthley_2006, Senter_2008, Schon_2018). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000009821	SCV004187785	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.
OMIM	RCV000009821	SCV000030042	pathogenic	Lynch syndrome 4	2005-05-01	no assertion criteria provided	literature only