ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2049C>T (p.Asn683=)

gnomAD frequency: 0.00004  dbSNP: rs752950007
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163909 SCV000214503 likely benign Hereditary cancer-predisposing syndrome 2014-06-03 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759918 SCV000889619 uncertain significance not provided 2018-01-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780630 SCV000918061 likely benign not specified 2019-03-12 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2049C>T alters a conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.3e-05 in 239440 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PMS2 causing Lynch Syndrome (6.3e-05 vs 0.00011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2049C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory in ClinVar has classified the variant as likely benign in 2014. Based upon our independent evaluation, no additional evidence supporting a pathogenic outcome have emerged between 2014 to present. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV001082995 SCV001009179 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-24 criteria provided, single submitter clinical testing
GeneDx RCV000759918 SCV001758538 benign not provided 2015-05-11 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000163909 SCV002530252 likely benign Hereditary cancer-predisposing syndrome 2021-05-29 criteria provided, single submitter curation
Color Diagnostics, LLC DBA Color Health RCV000163909 SCV004359566 likely benign Hereditary cancer-predisposing syndrome 2021-11-19 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001357657 SCV001553185 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The PMS2 p.Asn683=variant was not identified in the literature nor was it identified in the Cosmic, MutDB, Insight Colon Cancer Gene Variant, Zhejiang Colon Cancer, Mismatch Repair Genes Variant, and Insight Hereditary Tumors databases. The variant was identified the dbSNP (rs752950007) as “with Likely benign, uncertain significance allele”. The variant was also identified in ClinVar and in Clinvitae databases as likely benign by Ambry Genetics. The variant was identified in control databases in 15 of 239440 chromosomes at a frequency of 0.00006 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Asn683=variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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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