ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1013A>G (p.Asn338Ser) (rs63751467)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128912 SCV000172779 likely benign Hereditary cancer-predisposing syndrome 2018-01-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Co-occurence with mutation in same gene (phase unknown),Other data supporting benign classification
CSER_CC_NCGL; University of Washington Medical Center RCV000148621 SCV000190336 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research
Color RCV000128912 SCV000684708 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764485 SCV000895556 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000656860 SCV000279079 uncertain significance not provided 2017-12-20 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1013A>G at the cDNA level, p.Asn338Ser (N338S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). MLH1 Asn338Ser has been observed in at least three individuals with colorectal cancer, two of which were diagnosed <40 years of age and one in which tumor testing reportedly exhibited microsatellite instability (MSI-H status) and loss of the MLH1 and PMS2 proteins via immunohistochemistry (Rossi 2002, Hardt 2011, Rodr?guez-Soler 2013). In addition, this variant was observed in an individual with breast cancer with a family history of breast and ovarian cancer, as well as in two cases of epithelial ovarian cancer (Pal 2012, Caminsky 2016). MLH1 Asn338Ser was shown, through the use of a yeast two-hybrid assay, to exhibit MLH1/PMS2 interaction similar to that of wild-type, suggesting that it does not impact binding with PMS2 (Wang 2012). MLH1 Asn338Ser was observed at an allele frequency of 0.01% (16/126,584) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. MLH1 Asn338Ser is located within the N-terminal ATPase domain (Andersen 2012). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Asn338Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000524219 SCV000218987 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 338 of the MLH1 protein (p.Asn338Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs63751467, ExAC 0.009%). This variant has been observed in individuals affected with colorectal and ovarian cancer (PMID: 12095971, 23354017, 23047549, 21404117). Additionally, the variant has been observed in an individual affected with pancreatic ductal adenocarcinoma (PMID: 28767289). ClinVar contains an entry for this variant (Variation ID: 89605). Experimental studies have shown that this missense change does not impact the interaction between MLH1 and PMS2, and does not disrupt RNA splicing (PMID: 22252508, 18561205). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000220791 SCV000539649 uncertain significance not specified 2016-08-12 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: VUS by expert panel in 2013, no new evidence suggesting pathogenicity since then
Mendelics RCV000075074 SCV000838006 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000220791 SCV000601340 uncertain significance not specified 2017-07-14 criteria provided, single submitter clinical testing

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