ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.935T>C (p.Met312Thr) (rs530021751)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081365 SCV000253303 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-09-09 criteria provided, single submitter clinical testing
GeneDx RCV000588576 SCV000572445 uncertain significance not provided 2018-12-10 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.935T>C at the cDNA level, p.Met312Thr (M312T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has been observed in at least one individual with a history of breast cancer (Tung 2016). PMS2 Met312Thr was observed at an allele frequency of 0.09% (27/30780) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located within the ATPase domain (Guarne 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Met312Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000563510 SCV000663443 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-30 criteria provided, single submitter clinical testing The p.M312T variant (also known as c.935T>C), located in coding exon 9 of the PMS2 gene, results from a T to C substitution at nucleotide position 935. The methionine at codon 312 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species and threonine is the reference amino acid in several species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588576 SCV000697402 uncertain significance not provided 2016-05-03 criteria provided, single submitter clinical testing Variant summary: The PMS2 variant, c.935T>C (p.Met312Thr) causes a missense change involving a conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict 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 17/120588 (1/7092 including 1 homozygote), predominantly in the South Asian cohort, 17/16430 (1/966, 1 homozygote), which exceeds the estimated maxium expected allele frequency for a pathogenic PMS2 variant of 1/8802. Therefore, suggesting that the variant of interest is a polymorphism found in population(s) of South Asian origin. However, it needs to be noted that the capture of the PMS2 pseudogene in the ExAC population cannot be eliminated. The variant of interest has been reported in an affected individual via a publication, which co-occurred with a BARD1 variant, c.2183C>T (p.Ser728Phe), both classified as "unknown" by the authors. In addition, a clinical laboratory cites the variant with a classification of "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as VUS-possibly benign.
Color Health, Inc RCV000563510 SCV000910993 likely benign Hereditary cancer-predisposing syndrome 2017-06-07 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357920 SCV001553521 likely benign Carcinoma of colon no assertion criteria provided clinical testing The PMS2 p.Met312Thr variant was identified in 1 of 976 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Tung_20016_26976419). The variant was also identified in dbSNP (ID: rs530021751) “With Uncertain significance allele”, ClinVar (classified likely benign by Invitae and uncertain significance by GeneDx), Clinvitae (2x), and in control databases in 30 (1 homozygous) of 246124 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 3 of 5482 chromosomes (freq: 0.0005) and South Asian in 27 (1 homozygous) of 30780 chromosomes (freq: 0.0009); it was not observed in the African, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian and European Finnish populations. The variant was not found 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 by our laboratory in 1 individual with CRC at 28 years of age, co-occurring with a pathogenic MLH1 variant (c.1219C>T, p.Gln407X). The p.Met312 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of Thr to the protein; this information is not very predictive of 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 this variant meets our laboratory's criteria to be classified as likely benign.

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