Submissions for variant NM_000535.7(PMS2):c.1840A>T (p.Lys614Ter)

dbSNP: rs63750490

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076831	SCV000108318	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	nonsense/frameshift
Ambry Genetics	RCV000164595	SCV000215254	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-03	criteria provided, single submitter	clinical testing	The p.K614* pathogenic mutation (also known as c.1840A>T), located in coding exon 11 of the PMS2 gene, results from an A to T substitution at nucleotide position 1840. This changes the amino acid from a lysine to a stop codon within coding exon 11. This mutation has been detected in colorectal and endometrial cancer patients whose tumors demonstrated isolated absence of PMS2 by immunohistochemistry (Senter L et al. Gastroenterology 2008 Aug;135(2):419-28). It has also been identified in a homozygous state in an individual with features consistent with constitutional mismatch repair deficiency (CMMR-D) syndrome, including colorectal cancer and high grade astrocytoma before age 20y (Gururangan S et al. Neuro-oncology 2008 Feb;10(1):93-7). 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	RCV000216236	SCV000279146	pathogenic	not provided	2024-03-18	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 a personal or family history consistent with pathogenic variants in this gene (PMID: 18809606, 18602922, 25980754); Observed homozygous in an individual with features consistent with constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 17993636); Not observed at significant frequency in large population cohorts (gnomAD); 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: 25980754, 21376568, 25856668, 14574005, 22577899, 18809606, 25691505, 18602922, 31447099, 30787465, 33087929, 28888541, 36922933, 17993636)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540895	SCV000625560	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys614*) 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 constitutional mismatch repair deficiency syndrome and colorectal cancer and/or endometrial cancer (PMID: 17993636, 18602922, 21376568, 22577899, 22692065, 25856668). ClinVar contains an entry for this variant (Variation ID: 91318). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000164595	SCV000691046	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-05	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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of having Lynch syndrome (PMID: 18602922, 18809606, 25856668, 25980754). This variant has also been reported in homozygous individuals affected with constitutional mismatch repair deficiency (PMID: 17993636, 25691505). 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.
CSER _CC_NCGL, University of Washington	RCV000076831	SCV000864157	pathogenic	Lynch syndrome	2017-08-01	criteria provided, single submitter	research	Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 66 year old female with a personal history of uterine cancer and family history of colorectal cancer. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000216236	SCV000889610	pathogenic	not provided	2024-02-14	criteria provided, single submitter	clinical testing	The PMS2 c.1840A>T (p.Lys614*) variant causes the premature termination of PMS2 protein synthesis. This variant has been reported in the published literature in individuals and families with Lynch syndrome or Lynch-related cancers (PMIDs: 25980754 (2015), 18809606 (2008), 18602922 (2008), 17993636 (2008)), as well as in individuals with ovarian cancer (PMID: 31447099 (2019)) and breast cancer (PMID: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/BRCA1)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258087	SCV001434929	pathogenic	Lynch syndrome 4	2018-08-06	criteria provided, single submitter	clinical testing	The c.1840A>T (p.Lys614*) variant in the PMS2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated individuals with Lynch Syndrome related tumors (PMID 17993636, 18602922,25980754) or constitutional mismatch repair deficiency syndrome (PMID 17993636). Therefore, this c.1840A>T (p.Lys614*) variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280569	SCV001467772	pathogenic	Hereditary nonpolyposis colon cancer	2020-12-09	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1840A>T (p.Lys614X) 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 251450 control chromosomes. c.1840A>T has been reported in the literature in the heterozygous state in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and/or endometrial cancer (e.g. Senter_2008, Gururangan_2008, Yurgelun_2015). The variant has also been reported in the homozygous state in at least one individual affected by constitutional mismatch repair syndrome (e.g. Gururangan_2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sema4, Sema4	RCV000164595	SCV002530234	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-18	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV001258087	SCV004187683	pathogenic	Lynch syndrome 4	2023-09-21	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	RCV001258087	SCV004207877	pathogenic	Lynch syndrome 4	2022-11-13	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000076831	SCV004847563	pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Lys614X variant in PMS2 has been reported in 4 heterozygous individuals with colon cancer and 2 homozygous individuals with colorectal cancer ad astrocytomas (Yurgelun 2015, Herkert 2011, Senter 2008, Gururangan 2008). It segregated with PMS2-related cancer in one relative (Gururangan 2008). This variant was absent from large population studies and was classified as pathogenic on September 5, 2013 by the ClinGen-approved inSIGHT expert panel (ClinVar ID 91318). This nonsense variant leads to a premature termination codon at position 614, which is predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PM3, PS4_Supporting.
All of Us Research Program, National Institutes of Health	RCV000076831	SCV005429560	pathogenic	Lynch syndrome	2024-07-29	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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome or suspected of having Lynch syndrome (PMID: 18602922, 18809606, 25856668, 25980754). This variant has also been reported in homozygous individuals affected with constitutional mismatch repair deficiency (PMID: 17993636, 25691505). Tumor data from affected individuals has demonstrated loss of PMS2 protein via immunohistochemistry or high microsatellite instability (PMID: 17993636, 18809606). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000216236	SCV001553557	pathogenic	not provided		no assertion criteria provided	clinical testing	The PMS2 p.Lys614* variant was identified in 2 of 198 proband chromosomes (frequency: 0.01) from individuals or families with colorectal cancer (Senter 2008). The variant was also identified in 3 probands of consanguineous parents with constitutional mismatch repair deficiency syndrome (Baas 2013, Gururangan 2007). The variant was also identified in dbSNP (ID: rs63750490) as "With Pathogenic allele ", ClinVar (classified as Pathogenic by Invitae, Ambry Genetics, GeneDx, InSight and Color), Cosmic (1x in large intestine tissue), Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors Database (4x), databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Lys614* variant leads to a premature stop codon at position 614, 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 PMS2 associated cancers 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.