ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1004A>G (p.Asn335Ser) (rs200513014)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586586 SCV000149556 likely benign not provided 2021-06-03 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28195393, 28135145, 25256751, 24549055, 24728327, 28503720, 27153395, 28596308, 28874130, 28591191, 28873162, 30306255, 27535533, 11574484, 29625052, 31992580)
Invitae RCV001080700 SCV000166366 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115647 SCV000185908 likely benign Hereditary cancer-predisposing syndrome 2019-02-25 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other data supporting benign classification
Color Health, Inc RCV000115647 SCV000537521 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-27 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 335 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast, ovarian, pancreatic, and colorectal cancers (PMID: 24326041, 24549055, 27153395, 28135145, 28195393, 28503720, 28874130, 29945567, 30306255, 31992580, 32959997). However, tumors have not shown microsatellite instability (PMID 31391288) and segregation analysis was not supportive of pathogenicity (PMID 28195393). This variant has been identified in 77/282046 chromosomes (57/128908 Non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121835 SCV000601805 uncertain significance not specified 2017-04-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121835 SCV000697275 likely benign not specified 2020-10-23 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1004A>G (p.Asn335Ser) results in a conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 250652 control chromosomes, predominantly at a frequency of 0.00044 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1004A>G has been reported in the literature in individuals affected with colorectal cancer and breast and/or ovarian cancer (Harismendy_2013, Castera_2014, Tung_2014, Maxwell_2016, Yurgelun_2017, Rummel_2017, Hansen_2017, Feliubadalo_2017, Young_2018, Bonache_2018, Wang_2020). These reports however, do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven other ClinVar submitters (evaluation after 2014) cite the variant as benign /likely benign (n=2) or uncertain significance (n=9). One submission indicates the variant co-occurred with a mutation in another gene that clearly explains a proband's phenotype. Additional details regarding co-occurrence were not provided (submission from Ambry Genetics). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000121835 SCV000711439 uncertain significance not specified 2016-12-28 criteria provided, single submitter clinical testing The p.Asn335Ser variant in PMS2 has been reported in 1 individual who had underg one testing for a personal or family history of breast or ovarian cancer (Caster a 2014) and 1 healthy individual (Bodian 2014). This variant has been identified in 27/65558 (0.04%) European chromosomes by the Exome Aggregation Consortium (E xAC, http://exac.broadinstitute.org; dbSNP 200513014). Computational prediction tools and conservation analysis suggest that the p.Asn335Ser variant may impact the protein, though this information is not predictive enough to determine patho genicity. In summary, the clinical significance of the p.Asn335Ser variant is un certain.
PreventionGenetics,PreventionGenetics RCV000586586 SCV000806163 uncertain significance not provided 2016-12-22 criteria provided, single submitter clinical testing
Mendelics RCV000708986 SCV000838182 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000415644 SCV001137308 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000708986 SCV001450725 uncertain significance Lynch syndrome 2020-11-02 criteria provided, single submitter clinical testing The PMS2 c.1004A>G (p.Asn335Ser) missense change has a maximum subpopulation frequency of 0.044% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/7-6029571-T-C). Seven of seven in silico tools predict a damaging effect of this variant on protein function (PP3), but these predictions have not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer (PMID: 28195393, 28874130, 28135145, 29945567, 29684080), breast cancer (PMID: 32959997, 28503720, 28591191, 30306255, 25186627), and other cancers (PMID: 24549055, 29684080). The variant did not segregate with disease in one report (BS4_Supporting; PMID: 28195393). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3, BS4_Supporting.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285596 SCV001472056 uncertain significance none provided 2020-04-03 criteria provided, single submitter clinical testing The PMS2 c.1004A>G; p.Asn335Ser variant (rs200513014) is reported in the literature in individuals with hereditary breast and ovarian cancer syndrome (Castera 2014, Rummel 2017), and in individuals with Lynch syndrome (Hansen 2017, Rossi 2017); however, an affected relative did not carry the variant (Hansen 2017). This variant is reported in ClinVar (Variation ID: 127751). It is found in the general population with an overall allele frequency of 0.03% (77/282046 alleles). The asparagine at codon 335 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on the available information, the clinical significance of this variant is uncertain at this time. REFERENCES Castera L et al. Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. Eur J Hum Genet. 2014 Nov;22(11):1305-13. Hansen MF et al. Use of multigene-panel identifies pathogenic variants in several CRC-predisposing genes in patients previously tested for Lynch Syndrome. Clin Genet. 2017 Oct;92(4):405-414. Rossi BM et al. A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. BMC Cancer. 2017 Sep 5;17(1):623. Rummel SK et al. Contribution of germline mutations in cancer predisposition genes to tumor etiology in young women diagnosed with invasive breast cancer. Breast Cancer Res Treat. 2017 Aug;164(3):593-601.
Baylor Genetics RCV000415644 SCV001481209 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2019-09-30 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586586 SCV001747499 uncertain significance not provided 2021-06-01 criteria provided, single submitter clinical testing
ITMI RCV000121835 SCV000086033 not provided not specified 2013-09-19 no assertion provided reference population
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000415644 SCV000493783 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-03-30 no assertion criteria provided clinical testing
True Health Diagnostics RCV000115647 SCV000788098 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-08 no assertion criteria provided clinical testing
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249992 SCV001424006 uncertain significance Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354576 SCV001549224 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The PMS2 p.Asn335Ser variant was identified in 6 of 1000 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian, solid tumor, and colorectal cancer (Castera 2014, Hansen 2017, Le 2017, Rummel 2017, Stafford 2017, Rossi 2017). The variant was identified in our laboratory in a patient with a co-occuring pathogenic MLH1 variant suggesting that the PMS2 cp.Asn335Ser variant does not have clinical significance. The variant was also identified in the following databases: dbSNP (ID: rs200513014) as "With Uncertain significance allele", ClinVar (9x uncertain significance by LMM, GeneDx and 7 additional submitters, 1x likely benign by Ambry, and 1x as Benign by Invitae). The variant was identified in control databases in 78 of 276560 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Of note, in the European population, the variant was found in 59 of 126526 chromosomes (freq. 0.0005). The p.Asn335 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000586586 SCV001742441 uncertain significance not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000586586 SCV001800009 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000586586 SCV001955202 uncertain significance not provided no assertion criteria provided clinical testing

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