ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.383C>T (p.Ser128Leu) (rs116373169)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001084082 SCV000166385 benign Hereditary nonpolyposis colorectal neoplasms 2020-11-27 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 Co-occurence with mutation in same gene (phase unknown);Subpopulation frequency in support of benign classification
GeneDx RCV000200993 SCV000211588 likely benign not specified 2017-12-28 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.
PreventionGenetics,PreventionGenetics RCV000200993 SCV000304735 likely benign not specified criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 Health, Inc 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 Hereditary nonpolyposis colorectal cancer type 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 Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286560 SCV001473154 uncertain significance none provided 2019-09-13 criteria provided, single submitter clinical testing The PMS2 c.383C>T; p.Ser128Leu variant (rs116373169) is reported as benign/likely benign by multiple laboratories in ClinVar (Variation ID: 135943). This variant is found in the general African population with an allele frequency of 0.5% (136/24972 alleles, including 1 homozygote) in the Genome Aggregation Database. The serine at codon 128 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious. 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.
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 I 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.

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