Submissions for variant NM_000535.7(PMS2):c.2012C>T (p.Thr671Met)

gnomAD frequency: 0.00017  dbSNP: rs587780046

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000488189	SCV000149579	uncertain significance	not provided	2023-08-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26483394, 31422574, 22229248, 27449771, 28135145, 29101607, 29785153, 25186627, 31159747, 30613976, 34271781, 33120919, 26321251, 35372080, 35402282, 30113427, 35089076, 33471991, 11292842, 37534630, 35263119, 34326862)
Ambry Genetics	RCV000115670	SCV000186832	benign	Hereditary cancer-predisposing syndrome	2015-09-11	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000200451	SCV000255287	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000488189	SCV000575508	uncertain significance	not provided	2016-11-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000488189	SCV000601835	uncertain significance	not provided	2023-01-13	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00035 (29/83638 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with pancreatic cancer (PMIDs: 26483394 (2015) and 27449771 (2016)), breast cancer (PMIDs: 25186627 (2015), 29785153 (2018), 31159747 (2019), 31422574 (2019), 33120919 (2020), 35402282 (2022)), and colorectal cancer (PMIDs: 28135145 (2017), 34271781 (2021)). It has been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000515168	SCV000611421	uncertain significance	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2017-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212865	SCV000697320	uncertain significance	not specified	2023-01-23	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2012C>T (p.Thr671Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 168512 control chromosomes (gnomAD). The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is benign. However, this observation needs to be cautiously considered since sequence alignment analysis suggests that the variant lies within a region of the gene that has high homology with the PMS2 pseudogene. c.2012C>T has been reported in the literature in individuals affected with breast cancer, colorectal cancer, ovarian cancer or pancreatic cancer (e.g. Tung 2015, Hu 2016, Yang 2016, Yurgelun 2017, Goidescu 2018, Rizzolo_2019, Tsaousis_2019, Duzkale_2021, Sahin_2022, Abdel-Razeq_2022, Dorling_2021, Delahunty_2022,) but has also been reported in individual(s) without a cancer diagnosis (e.g. Kraemer_2019). One of the reported colorectal cancer patients had a co-occurring pathogenic variant (KRAS c.34G>T, p.Gly12Cys) while the patient's tumor was determined to be MMR proficient and microsatellite stable (Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Sixteen ClinVar submitters have assessed the variant since 2014: fifteen classified the variant as VUS and one as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneKor MSA	RCV000115670	SCV000822126	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000708981	SCV000838173	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000987820	SCV001137284	uncertain significance	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000987820	SCV001324104	uncertain significance	Lynch syndrome 4	2019-11-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000488189	SCV002009106	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212865	SCV002072015	uncertain significance	not specified	2021-06-09	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.2012C>T, in exon 12 that results in an amino acid change, p.Thr671Met. This sequence change has been described in gnomAD with a frequency of 0.035% in the Non-Finnish European sub-population (dbSNP rs587780046). The p.Thr671Met change affects a poorly conserved amino acid residue located in a domain of the PMS2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr671Met substitution. The c.2012C>T sequence change has been reported in the literature in individuals affected with breast cancer, colorectal cancer or pancreatic cancer (PMIDs: 25186627, 26483394, 27449771, 28135145, 29785153, 30613976, 31159747) but has also been reported in individuals without a cancer diagnosis (PMID: 31422574). One of the reported colorectal cancer patients also carried a pathogenic variant in the KRAS gene (c.34G>T, p.Gly12Cys). The patient's tumor was determined to be MMR proficient and microsatellite stable (PMID: 28135145). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr671Met change remains unknown at this time.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000987820	SCV002525945	uncertain significance	Lynch syndrome 4	2022-03-17	criteria provided, single submitter	clinical testing	The PMS2 c.2012C>T (p.Thr671Met) missense change has a maximum subpopulation frequency of 0.035% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/7-6022617-G-A?dataset=gnomad_r2_1). This variant is located in exon 12 of the PMS2 gene and data in this region are not considered reliable due to high pseudogene homology. This variant was reported in 2 of 1,058 individuals with colorectal cancer (PMID: 28135145). One of the individuals also harbored a pathogenic germline variant in MUTYH (c.891+3A>C). The tumor of this individual was determined to be MMR proficient and microsatellite stable (PMID: 28135145). This variant has also been reported in individuals with breast cancer (PMID: 25186627, 29785153, 30613976) and pancreatic cancer (PMID: 26483394, 27449771). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: not criteria met.
Sema4, Sema4	RCV000115670	SCV002530250	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-22	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212865	SCV002550696	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000987820	SCV002580904	uncertain significance	Lynch syndrome 4	2022-07-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149799	SCV003837728	uncertain significance	Breast and/or ovarian cancer	2022-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000987820	SCV004205364	uncertain significance	Lynch syndrome 4	2023-10-20	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000488189	SCV004223986	uncertain significance	not provided	2022-11-04	criteria provided, single submitter	clinical testing	BP4
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115670	SCV004228154	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115670	SCV004359572	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-02	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 671 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 25186627, 29785153, 31422574, 33120919), colorectal (PMID: 28135145), or pancreatic cancer (PMID: 2648339). This variant has been identified in 35/199754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). However, this observed allele frequency is not considered reliable, because the gnomAD dataset does not disambiguate possible interference from homologous sequences in the PMS2CL pseudogene. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Pathway Genomics	RCV000144642	SCV000189969	uncertain significance	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000488189	SCV001552727	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PMS2 p.Thr671Met variant was identified in 3 of 260 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer of Romanian ethnicity (Goidescu 2017). The variant was also identified in dbSNP (ID: rs587780046) as with uncertain significance allele; and in ClinVar and Clinvitae databases as benign by Ambry Genetics and uncertain significance by Invitae, Praxis fuer Humangenetik Tuebingen, Quest Diagnostics - Nichols Institute San Juan Capistrano, Fulgent Genetics, GeneDx and Pathway Genomics. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was identified in control databases in 34 of 195042 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include other in 3 of 5030 chromosomes (freq: 0.0006), European Non-Finnish in 27 of 81252 chromosomes (freq: 0.0003), East Asian in 2 of 13498 chromosomes (freq: 0.0001), and South Asian in 2 of 23600 chromosomes (freq: 0.0001), while the variant was not observed in the African, Latino, Ashkenazi Jewish, European Finnish, populations. The p.Thr671 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
GenomeConnect - Invitae Patient Insights Network	RCV003483476	SCV004228731	not provided	Lynch syndrome; Mismatch repair cancer syndrome 4		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 07-28-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.