ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1609G>A (p.Glu537Lys) (rs115052399)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000127463 SCV000171030 benign not specified 2014-01-15 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 RCV000165452 SCV000216182 benign Hereditary cancer-predisposing syndrome 2014-11-18 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 RCV001082898 SCV000262253 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-04 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000204752 SCV000469726 likely benign Hereditary nonpolyposis colorectal cancer type 4 2018-01-12 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.
Color Health, Inc RCV000165452 SCV000686144 benign Hereditary cancer-predisposing syndrome 2015-01-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590728 SCV000697303 likely benign not provided 2016-06-15 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1609G>A (p.Glu537Lys) variant causes a missense change involving a non-conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 124/120170 (1 homozygote, 1/968), predominantly in the African cohort, 122/10000 (1 homozygote, 1/81), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic PMS2 variant of 1/8802 (0.0001136). Even though this observed frequency is higher than expected for the pathogenic variant, we must use controls data with caution due to presence of a pseudogene. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; however, reputable clinical diagnostic laboratories cite the variant as "benign." Therefore, taking all available lines of evidence, the variant of interest has been classified as Likely Benign.
PreventionGenetics,PreventionGenetics RCV000127463 SCV000806182 benign not specified 2017-04-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000127463 SCV000859816 benign not specified 2018-03-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285703 SCV001472179 benign none provided 2020-05-05 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355044 SCV001549806 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The PMS2 p.Glu537Lys variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs115052399) as With other allele, and in ClinVar (classified as benign by GeneDx, Ambry genetics, Invitae). The variant was identified in control databases in 328 (2 homozygous) of 276484 chromosomes at a frequency of 0.001 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 311 of 23762 chromosomes (freq: 0.013). The p.Glu537 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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