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

gnomAD frequency: 0.00001  dbSNP: rs587778617

Total submissions: 14

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, Mass General Brigham 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	2022-04-06	criteria provided, single submitter	clinical testing	The p.R421* pathogenic mutation (also known as c.1261C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1261. This changes the amino acid from an arginine to a stop codon within coding exon 11. This pathogenic alteration was present in 1/130 European families with PMS2 mutations meeting either Bethesda criteria or "MSI-testing-indicated-by-a-pathologist" criteria (Suerink M et al. Genet. Med. 2016 Apr;18:405-9). 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.
GeneDx	RCV000219846	SCV000279393	pathogenic	not provided	2022-09-05	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with suspected Lynch Syndrome (Vaughn et al., 2013; Suerink et al., 2016; Wang et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31159747, 24728327, 26110232, 23012243, 30787465, 31992580, 33259954, 33693762)
Invitae	RCV000627692	SCV000285057	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-06	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. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer and/or suspected Lynch syndrome (PMID: 23012243, 26110232). ClinVar contains an entry for this variant (Variation ID: 91299). For these reasons, this variant has been classified as Pathogenic.
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 Diagnostics, LLC DBA Color Health	RCV000223405	SCV001347955	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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	RCV001255553	SCV001432025	pathogenic	Hereditary nonpolyposis colon cancer	2023-08-04	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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251060 control chromosomes. 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. The following publications have been ascertained in the context of this evaluation (PMID: 23012243, 29345684, 26110232, 31159747, 31300551). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000786880	SCV004187673	pathogenic	Lynch syndrome 4	2023-09-20	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV000786880	SCV004207837	pathogenic	Lynch syndrome 4	2023-05-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000219846	SCV004218948	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of PMS2 protein synthesis. The frequency of this variant in the general population, 0.0000066 (1/152196 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMID: 31300551 (2020), 31159747 (2019), 29345684 (2018)), and Lynch syndrome (PMID: 26110232 (2016), 23012243 (2013)). Based on the available information, this variant is classified as pathogenic.
ITMI	RCV000121843	SCV000086041	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353689	SCV000592931	pathogenic	Endometrial carcinoma		no assertion criteria provided	clinical testing	The p.ARG421X variant was identified as a nonsense mutation in the paper by Topp (2014). The variant was also identified in COSMIC in large intestine tissue and InSiGHT Colon Cancer databases. In ClinVar the variant was classified as pathogenic by InSiGHT. This residue is not conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) have not provided predictions regarding the impact to the protein. In summary, based on the above information this variant meets our laboratory's criteria to be classified as pathogenic.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000786880	SCV000925779	likely pathogenic	Lynch syndrome 4	2018-09-27	no assertion criteria provided	clinical testing