Submissions for variant NM_000535.7(PMS2):c.383C>T (p.Ser128Leu)

gnomAD frequency: 0.00177  dbSNP: rs116373169

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001084082	SCV000166385	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000128980	SCV000172866	likely benign	Hereditary cancer-predisposing syndrome	2018-12-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
GeneDx	RCV000587673	SCV000211588	likely benign	not provided	2021-09-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31433215, 28211887, 28765196, 28873162, 27930734, 20205264)
PreventionGenetics, part of Exact Sciences	RCV000200993	SCV000304735	likely benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000587673	SCV000333808	uncertain significance	not provided	2015-09-11	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000200993	SCV000596471	benign	not specified	2017-06-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128980	SCV000686199	likely benign	Hereditary cancer-predisposing syndrome	2015-10-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587673	SCV000697367	likely benign	not provided	2016-02-01	criteria provided, single submitter	clinical testing	Variant summary: The c.383C>T variant affects a conserved nucleotide, resulting in amino acid change from Ser to Leu. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant is found in 92/121400 control chromosomes at a frequency of 0.0007578, which is about 7 times of maximal expected frequency of a pathogenic allele (0.0001136), suggesting this variant is benign. Sequence alignment suggests alleles identified in ExAC controls are unlikely from PMS2 pseudogenes. In addition, multiple clinical laboratories/literature classified this variant as benign/likely benign/polymorphisms. Taken together, this variant was classified as likely benign.
Counsyl	RCV000662720	SCV000785474	likely benign	Lynch syndrome 4	2017-08-18	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758689	SCV000887461	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	PMS2 NM_000535.5:c.383C>T has a 14.1% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214.
Mendelics	RCV000662720	SCV001137327	likely benign	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587673	SCV001473154	uncertain significance	not provided	2022-12-28	criteria provided, single submitter	clinical testing	The PMS2 c.383C>T; p.Ser128Leu variant (rs116373169) is reported in the literature in an individual with suspected Lynch syndrome, although its clinical significance in this individual was uncertain (Borras 2017). This variant is found in the African population with an allele frequency of 0.5% (136/24972 alleles, including 1 homozygote) in the Genome Aggregation Database, and it is reported as benign/likely benign by multiple laboratories in ClinVar (Variation ID: 135943). The serine at codon 128 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.413). Our laboratory has identified this variant in an individual who also carried a pathogenic truncating PMS2 variant. Although the evidence suggests this variant may be likely benign, there is currently insufficient information to classify with certainty. Therefore, based on available information, the clinical significance of this variant is uncertain at this time. References: Borras E et al. In Silico Systems Biology Analysis of Variants of Uncertain Significance in Lynch Syndrome Supports the Prioritization of Functional Molecular Validation. Cancer Prev Res (Phila). 2017 Oct;10(10):580-587. PMID: 28765196.
Sema4, Sema4	RCV000128980	SCV002530338	likely benign	Hereditary cancer-predisposing syndrome	2021-06-23	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662720	SCV004019783	benign	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000200993	SCV004025130	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000587673	SCV004223992	uncertain significance	not provided	2022-03-09	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492544	SCV004239598	likely benign	Breast and/or ovarian cancer	2022-11-22	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000128980	SCV000788115	likely benign	Hereditary cancer-predisposing syndrome	2017-09-29	no assertion criteria provided	clinical testing
Ding PR Lab, Sun Yat-sen University Cancer Center	RCV001093681	SCV001250862	uncertain significance	Lynch syndrome 1		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356925	SCV001552219	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Ser128Leu variant was identified in 1 of 290 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome (Vaughn 2010). The variant was also identified in dbSNP (ID: rs116373169) as "With other allele", ClinVar (classified as benign by Invitae and one other submitter; as likely benign by Ambry Genetics, GeneDx, and five other submitters; and as uncertain significance by one submitter), Cosmic (1x in skin tissue), and MutDB. The variant was not identified in COGR, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors database. The variant was identified in control databases in 188 of 276898 chromosomes (1 homozygous) at a frequency of 0.0007, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 134 of 24038 chromosomes (freq: 0.006), Latino in 3 of 34420 chromosomes (freq: 0.00009), European in 43 of 126388 chromosomes (freq: 0.0003), East Asian in 7 of 18870 chromosomes (freq: 0.0004), and South Asian in 1 of 30782 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Ashkenazi Jewish, or Finnish populations. The p.Ser128 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.