ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1723A>G (p.Asn575Asp) (rs142506484)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212863 SCV000149573 uncertain significance not provided 2021-05-25 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26976419, 27978560, 25980754)
Ambry Genetics RCV000115664 SCV000186208 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-13 criteria provided, single submitter clinical testing The p.N575D variant (also known as c.1723A>G), located in coding exon 11 of the PMS2 gene, results from an A to G substitution at nucleotide position 1723. The asparagine at codon 575 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was detected in a cohort of 1260 individuals with a Lynch syndrome-related tumor and/or colon polyps who underwent a multigene hereditary cancer panel (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20) and was reported in a woman with MMR-proficient right-sided colon cancer diagnosed at age 48 (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). This alteration has also been reported in a cohort of 488 patients with stages I to III breast cancer diagnosed over age 50 who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8). This amino acid position is not well conserved in available vertebrate 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.
Invitae RCV000195776 SCV000254606 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-13 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 575 of the PMS2 protein (p.Asn575Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs142506484, ExAC 0.005%). This variant has been reported in an individual affected with breast cancer (PMID: 26976419) and an individual undergoing Lynch syndrome testing (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127766). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000115664 SCV000903240 likely benign Hereditary cancer-predisposing syndrome 2016-01-07 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212863 SCV001552224 uncertain significance not provided no assertion criteria provided clinical testing The PMS2 p.Asn575Asp variant was identified in 2 of 1876 proband chromosomes (frequency: 0.001) from individuals or families with breast or colon cancer (Pearlman 2017, Tung 2016). The variant was also identified in dbSNP (ID: rs142506484) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance GeneDx, Ambry Genetics and Invitae). The variant was not identified COGR, Cosmic, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in control databases in 4 of 246168 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 4 of 111660 chromosomes (freq: 0.00004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asn575 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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