ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.379G>A (p.Ala127Thr)

gnomAD frequency: 0.00010  dbSNP: rs114090343
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000121857 SCV000171046 benign not specified 2014-06-02 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 RCV000129112 SCV000183825 likely benign Hereditary cancer-predisposing syndrome 2018-11-09 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.
Invitae RCV001084398 SCV000218861 benign Hereditary nonpolyposis colorectal neoplasms 2024-01-29 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001095167 SCV000469740 likely benign Lynch syndrome 4 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Genetic Services Laboratory, University of Chicago RCV000121857 SCV000596472 likely benign not specified 2016-05-25 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000129112 SCV000686198 likely benign Hereditary cancer-predisposing syndrome 2015-04-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590269 SCV000697366 likely benign not provided 2017-05-15 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000168196 SCV000887462 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing PMS2 NM_000535.5:c.379G>A has a 70.8% probability of pathogenicity based on combining prior probability from public data with likelihood ratios of 1.56 and 1.56 to 1, generated from evidence of seeing this as a somatic mutation in two independent tumors without loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590269 SCV000889626 benign not provided 2022-08-11 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000121857 SCV001160411 likely benign not specified 2019-03-27 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000129112 SCV002530337 benign Hereditary cancer-predisposing syndrome 2020-12-28 criteria provided, single submitter curation
PreventionGenetics, part of Exact Sciences RCV003945100 SCV004756988 likely benign PMS2-related disorder 2020-04-16 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
ITMI RCV000121857 SCV000086059 not provided not specified 2013-09-19 no assertion provided reference population
Ding PR Lab, Sun Yat-sen University Cancer Center RCV001093698 SCV001250882 uncertain significance Lynch syndrome 1 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000590269 SCV001550059 likely benign not provided no assertion criteria provided clinical testing The PMS2 p.Ala127Thr variant was not identified in the literature nor was it identified in the following databases: the COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant, Zhejiang Colon Cancer, Mismatch Repair Genes Variant, or Insight Hereditary Tumors database. The variant was identified in dbSNP (ID: rs114090343); in ClinVar and Clinvitae databases as benign by GeneDx and Invitae; as likely benign by Ambry Genetics, Genetic Services laboratory, University of Chicago; and uncertain significance by Illumina Clinical Services. The variant was identified in control databases in 119 of 276900 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency variant in certain populations (Genome Aggregation Database Feb 27, 2017). Observation by population include: “other” in 1 of 6460 chromosomes (freq: 0.0002), European Non-Finnish in 3 of 126390 chromosomes (freq: 0.00002), East Asian in 109 of 18868 chromosomes (freq: 0.005777), and South Asian in 6 of 30782 chromosomes (freq: 0.000195). The variant was not observed in the African, Latino, Ashkenazi Jewish, European Finnish, populations. It was observed in homozygous form in an individual from our lab without features of biallelic mismatch repair syndrome increasing the likelihood this variant is benign. The p.Ala127Thr 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. 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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