ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1711C>A (p.Leu571Ile) (rs63750055)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076821 SCV000108308 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research MAF >1% in African population
GeneDx RCV000121847 SCV000171033 benign not specified 2013-12-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000162433 SCV000212780 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Invitae RCV001081763 SCV000262182 benign Hereditary nonpolyposis colorectal neoplasms 2020-11-22 criteria provided, single submitter clinical testing
Vantari Genetics RCV000162433 SCV000267073 likely benign Hereditary cancer-predisposing syndrome 2016-01-22 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000034621 SCV000511461 likely benign not provided 2017-02-16 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
Genetic Services Laboratory, University of Chicago RCV000121847 SCV000596467 benign not specified 2017-11-30 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162433 SCV000686155 benign Hereditary cancer-predisposing syndrome 2014-12-09 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000121847 SCV000701855 likely benign not specified 2016-10-06 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000625102 SCV000743779 benign Hereditary nonpolyposis colorectal cancer type 4 2016-03-15 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000625102 SCV000745190 likely benign Hereditary nonpolyposis colorectal cancer type 4 2016-07-19 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000121847 SCV000806186 benign not specified 2017-01-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282411 SCV001158695 benign none provided 2020-02-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000625102 SCV001326300 likely benign Hereditary nonpolyposis colorectal cancer type 4 2018-04-16 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034621 SCV000043423 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
ITMI RCV000121847 SCV000086047 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000162433 SCV000788108 benign Hereditary cancer-predisposing syndrome 2017-11-30 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357078 SCV001552416 likely benign Carcinoma of colon no assertion criteria provided clinical testing The PMS2 p.Leu571Ile variant was identified 5 of 2018 proband chromosomes (frequency: 0.002) from Dutch and American individuals or families with Lynch Syndrome, suspected Lynch Syndrome, or individuals being ascertained for atherosclerosis phenotypes (van der Klift 2016, Johnston 2012, Clendenning 2006). The variant was identified in the following databases: dbSNP (ID: rs63750055) as “other”, ClinVar (classified as likely benign, reviewed by an expert panel; classified as likely benign by InSIGHT, Vantari Genetics, Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics; benign by GeneDx, Ambry Genetics, Invitae; uncertain significance by Biesecker Lab/Human Development Section-NIH; and classification not provided by ITMI), Clinvitae (4X), Insight Colon Cancer Gene Variant Database (3X), and Insight Hereditary Tumors Database; but was not identified in COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database and the Mismatch Repair Genes Variant Database. The variant was identified in control databases in 760 (10 homozygous) of 277148 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following population at a frequency greater than 1%: African in 506 (10 homozygous) of 23994 chromosomes (freq: 0.021). The p.Leu571 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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. The variant was identified by our laboratory in an individual with a co-occurring pathogenic variant (PMS2, c.2276-?_2445+?del), increasing the likelihood this variant does not have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000034621 SCV001797961 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000034621 SCV001808050 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000034621 SCV001917463 likely benign not provided no assertion criteria provided clinical testing

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