ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1709A>G (p.Asn570Ser) (rs375853155)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586361 SCV000211114 uncertain significance not provided 2018-10-24 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1709A>G at the cDNA level, p.Asn570Ser (N570S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant was observed in a woman with endometrial cancer whose tumor exhibited normal expression of mismatch repair proteins on immunohistochemistry (Frolova 2015). This variant was also observed in an individual undergoing multigene cancer panel testing based on a history of a Lynch-related cancer and/or polyps (Yurgelun 2015), as well as identified in 1/43 healthy African 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. MLH1 Asn570Ser was observed at an allele frequency of 0.03% (6/24,022) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the region of interaction with EXO1, PMS2, MLH3, and PMS1 (Raevaara 2005, Kansikas 2011, Anderson 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 Asn570Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160540 SCV000216542 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000233319 SCV000284027 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-06 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 570 of the MLH1 protein (p.Asn570Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs375853155, ExAC 0.03%). This variant has been reported in the literature in an individual with endometrial cancer (PMID: 25617771), and an individual tested for Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 134658). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, 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.
Counsyl RCV000411716 SCV000488243 uncertain significance Lynch syndrome II 2016-02-02 criteria provided, single submitter clinical testing
Color RCV000160540 SCV000689829 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586361 SCV000696121 uncertain significance not provided 2016-12-22 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1709A>G (p.Asn570Ser) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 4/121248 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586361 SCV001134296 uncertain significance not provided 2019-07-04 criteria provided, single submitter clinical testing
Mendelics RCV000411716 SCV001136420 uncertain significance Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
ITMI RCV000121361 SCV000085542 not provided not specified 2013-09-19 no assertion provided reference population

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