Submissions for variant NM_000535.7(PMS2):c.1261C>T (p.Arg421Ter) (rs587778617)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076804	SCV000108286	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000076804	SCV000271438	pathogenic	Lynch syndrome	2016-03-03	criteria provided, single submitter	clinical testing	The p.Arg421X variant in PMS2 has been reported in one carrier with unspecified phenotype (Suerink 2015), and was absent from large population studies. This non sense variant leads to a premature termination codon at position 421, which is p redicted to lead to a truncated or absent protein. Heterozygous loss of function of the PMS2 gene is an established disease mechanism in Lynch syndrome. In summ ary, this variant meets our criteria to be classified as pathogenic for Lynch sy ndrome in an autosomal dominant manner based upon the predicted impact to the pr otein.
Ambry Genetics	RCV000223405	SCV000276002	pathogenic	Hereditary cancer-predisposing syndrome	2019-03-14	criteria provided, single submitter	clinical testing	Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx	RCV000219846	SCV000279393	pathogenic	not provided	2018-11-20	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted PMS2 c.1261C>T at the cDNA level and p.Arg421Ter (R421X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in at least two individuals with suspected Lynch Syndrome (Vaughn 2013, Suerink 2015). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). Based on current information, we consider this variant to be pathogenic.
Invitae	RCV000627692	SCV000285057	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2019-11-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg421*) 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 observed in individuals with colorectal cancer and/or suspected Lynch syndrome (PMID: 23012243, 26110232). ClinVar contains an entry for this variant (Variation ID: 91299). 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	RCV000076804	SCV000592931	pathogenic	Lynch syndrome	2015-01-13	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000223405	SCV000821766	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This is a point mutation replacing one nucleotide in the position 1261 of the PMS2 gene, leading in the replacement of Arginine with a termination stop codon in the position 421 of the PMS2 protein. The resulting protein is truncated and non functional. This particular variant has been described in international literature in families with colorectal cancer and/or Lynch syndrome (PMID: 23012243, PMID: 26110232). The mutation database ClinVar contains an entry for this variant (Variation ID: 91299).
Color	RCV000223405	SCV001347955	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV001255553	SCV001432025	pathogenic	Hereditary nonpolyposis colon cancer	2020-08-25	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1261C>T (p.Arg421X) 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 251060 control chromosomes (gnomAD). c.1261C>T has been reported in the literature in individuals with suspected Hereditary Nonpolyposis Colorectal Cancer (e.g. Vaughn_2013, Suerink_2016). It has also been reported by different studies in a number of individuals affected with breast cancer (e.g. Roberts_2018, Tsaousis_2019, Fostira_2020), with one of the studies concluding that pathogenic variants in the PMS2 gene are associated with an increased risk for breast cancer following retrospective review of patient data (Roberts_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ITMI	RCV000121843	SCV000086041	not provided	not specified	2013-09-19	no assertion provided	reference population
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare	RCV000786880	SCV000925779	likely pathogenic	Hereditary nonpolyposis colorectal cancer type 4	2018-09-27	no assertion criteria provided	clinical testing