ClinVar Miner

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

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586586 SCV000149556 uncertain significance not provided 2019-01-16 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1004A>G at the cDNA level, p.Asn335Ser (N335S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant was reported in a familial colorectal cancer patient, but was absent in an affected relative (Hansen 2017), and has been observed in other individuals with suspected Lynch syndrome and/or mismatch repair (MMR)-deficient tumors (Le 2017, Rossi 2017, Yurgelun 2017). PMS2 Asn335Ser has also been observed in individuals with a personal history of breast or ovarian cancer (Castera 2014, Maxwell 2016, Rummel 2017, Stafford 2017), and in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in the Bodian study were younger than 50 years old; thus, the unaffected status of this individual may not be significant. PMS2 Asn335Ser was observed at an allele frequency of 0.05% (59/126,526) in individuals of European (non-Finnish) ancestry in large population cohorts (Lek 2016). PMS2 Asn335Ser is located in 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 Asn335Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000586586 SCV000166366 benign not provided 2019-03-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115647 SCV000185908 likely benign Hereditary cancer-predisposing syndrome 2018-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,Other data supporting benign classification
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000415644 SCV000493783 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-03-30 criteria provided, single submitter clinical testing
Color RCV000115647 SCV000537521 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121835 SCV000601805 uncertain significance not specified 2017-04-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000121835 SCV000697275 likely benign not specified 2019-02-24 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, S5 domain 2-like 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 276560 control chromosomes. The observed variant frequency is approximately 2.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is benign. 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). These reports 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. Ten ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as likely benign/benign and eight times as uncertain significance. One submission indicates the variant co-occurred with a mutation in another gene that clearly explains a proband's phenotype, however, it is unclear whether this co-occurrence was an internal observance (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,; 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
ITMI RCV000121835 SCV000086033 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000115647 SCV000788098 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-08 no assertion criteria provided clinical testing

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