Submissions for variant NM_000535.7(PMS2):c.943C>T (p.Arg315Ter)

gnomAD frequency: 0.00001  dbSNP: rs200640585

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076901	SCV000108398	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000212858	SCV000149620	pathogenic	not provided	2021-08-04	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; Observed in individuals with MSI-H and/or PMS2 absent colorectal cancer (Vaughn 2010, Borras 2013, Shia 2013, Hinrichsen 2015, Goodenberger 2016, Sugano 2016, Wang 2020); Published functional studies demonstrate a damaging effect: loss of PMS2 expression and reduced MMR activity (Hinrichsen 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 32885271, 32719484, 25477341, 23709753, 20205264, 22918162, 25856668, 27589204, 31992580, 31784482, 31297337, 30521064, 26681312, 28724667, 25111426, 26046366, 25430799, 25525159, 25637381)
Ambry Genetics	RCV000115711	SCV000212770	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-27	criteria provided, single submitter	clinical testing	The p.R315* pathogenic mutation (also known as c.943C>T), located in coding exon 9 of the PMS2 gene, results from a C to T substitution at nucleotide position 943. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been reported in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome; several whose tumors demonstrated high microsatellite instability and/or absent PMS2 by immunohistochemistry (IHC) (Vaughn CP et al. Hum Mutat, 2010 May;31:588-93; Shia J et al. Mod. Pathol., 2013 Jan;26:131-8; Borràs E et al. J Med Genet, 2013 Aug;50:552-63; Goldberg Y et al. Clin Genet, 2015 Jun;87:549-53; Sugano K et al. Cancer Sci, 2016 Nov;107:1677-1686; Goodenberger ML et al. Genet Med, 2016 Jan;18:13-9; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Guo X et al. Mol Genet Genomic Med, 2019 06;7:e721; Maynard H et al. Cancer, 2020 01;126:1995-2002; Wang Q et al. J Med Genet, 2020 07;57:487-499; Choi YY et al. Sci Rep, 2021 07;11:14807). This mutation was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome. The individual was diagnosed with breast cancer at age 44 (Lerner-Ellis J et al. J Cancer Res Clin Oncol. 2021 147, 871–879). Pathogenicity of this mutation has been supported by a functional assay showing reduced mismatch repair activity in vitro and lack of full length PMS2 protein expression (Hinrichsen I et al. Carcinogenesis. 2015 Feb;36:202-11). 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.
Invitae	RCV000524484	SCV000261298	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg315*) 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 present in population databases (rs200640585, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and colon cancer (PMID: 20205264, 22918162, 23709753, 25856668, 27589204). ClinVar contains an entry for this variant (Variation ID: 91382). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000576503	SCV000677745	pathogenic	Lynch syndrome 4	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115711	SCV000691128	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 9 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 been reported in individuals affected with Lynch syndrome (PMID: 30376427) and colorectal cancer with tumors showing loss of PMS2 expression and/or microsatellite instability (PMID: 20205264, 22918162, 23709753, 25856668, 27589204). This variant has also been reported in an individual affected with breast cancer (PMID: 28724667). This variant has been identified in 5/282632 chromosomes 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212858	SCV000888422	pathogenic	not provided	2017-11-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763587	SCV000894426	pathogenic	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000076901	SCV001338126	pathogenic	Lynch syndrome	2020-01-31	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.943C>T (p.Arg315X) 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 allele was found at a frequency of 1.6e-05 in 251270 control chromosomes. c.943C>T has been reported in the literature in individuals affected with Lynch Syndrome or breast cancer (Susswein_2016, Latham_2019). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000212858	SCV001502552	pathogenic	not provided	2020-12-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000212858	SCV002018888	pathogenic	not provided	2022-11-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115711	SCV002530410	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-25	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000576503	SCV004019893	pathogenic	Lynch syndrome 4	2023-04-05	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	RCV000576503	SCV004205420	pathogenic	Lynch syndrome 4	2023-10-03	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148734	SCV000190469	pathogenic	Colorectal cancer, non-polyposis	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354630	SCV001549291	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Arg315* variant was identified in 5 of 2648 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome (Borras 2013, Goldberg 2015, Goodenberger 2016, Sugano 2016, Vaughn 2010). The variant was also identified in dbSNP (ID: rs200640585) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and four other submitters). The variant was identified in control databases in 6 of 277038 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24022 chromosomes (freq: 0.00004), European in 3 of 126694 chromosomes (freq: 0.00002), Ashkenazi Jewish in 1 of 10150 chromosomes (freq: 0.0001), and East Asian in 1 of 18866 chromosomes (freq: 0.00005); it was not observed in the Other, Latino, Finnish, or South Asian populations. The p.Arg315* variant leads to a premature stop codon at position 315, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Laboratory for Genotyping Development, RIKEN	RCV003162501	SCV002758146	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research