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 2019-07-24 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with endometrial cancer whose tumor demonstrated normal mismatch repair protein expression as well as an individual undergoing multigene cancer panel testing due to a history of a Lynch-related cancer and/or polyps (Frolova 2015, Yurgelun 2015); This variant is associated with the following publications: (PMID: 25980754, 24728327, 25617771)
Ambry Genetics RCV000160540 SCV000216542 likely benign Hereditary cancer-predisposing syndrome 2020-02-10 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign)
Invitae RCV000233319 SCV000284027 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-30 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 C1). 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 Health, Inc RCV000160540 SCV000689829 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-14 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 570 of the MLH1 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 endometrial cancer (PMID: 25617771) and Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has also been identified in 8/282582 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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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