ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.191A>G (p.Asn64Ser) (rs63750952)

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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 RCV000217492 SCV000276267 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000584818 SCV000692543 uncertain significance Global developmental delay; Choreoathetosis; Aqueductal stenosis 2016-03-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513562 SCV000609098 likely pathogenic not provided 2017-05-31 criteria provided, single submitter clinical testing
Color RCV000217492 SCV000684783 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Counsyl RCV000490571 SCV000611601 uncertain significance Lynch syndrome I 2017-06-29 criteria provided, single submitter clinical testing
GeneDx RCV000513562 SCV000211108 uncertain significance not provided 2018-05-22 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.191A>G at the cDNA level and p.Asn64Ser (N64S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). MLH1 Asn64Ser has been observed in affected individuals and families meeting clinical diagnostic criteria for Hereditary Nonpolyposis Colorectal Cancer (Wijnen 1997, Spaepen 2006, Hardt 2011). In a colorectal cancer kindred reported by Spaepen et al. (2006) this variant was reported to segregate with disease, with one studied tumor demonstrating microsatellite instability but normal MLH1 protein expression. Of note, age of cancer diagnosis at study enrollment was not provided in this report. Additionally, in the kindred reported by Hardt et al. (2011), MLH1 Asn64Ser co-occurred with a second MLH1 missense variant, His329Pro. In this family, MLH1 Asn64Ser was present in the proband's unaffected 72-year-old mother, and His329Pro either occurred de novo or was inherited from the proband's father, who was reportedly diagnosed with colon and stomach cancers at age 47 but whose MLH1 status was unknown. The authors also noted that His329Pro was the sole variant present in two other individuals in their cohort with early-onset colorectal cancer, with both tumors demonstrating microsatellite instability and absent MLH1 protein expression. These combined data led Hardt et al. to conclude that MLH1 Asn64Ser, on its own, is unlikely to be disease-causing. MLH1 Asn64Ser was not observed at a significant frequency in large population cohorts (Lek 2016). This variant is located in the ATP-binding and hydrolysis domain (Raevaara 2005, Kansikas 2011, Andersen 2012). While in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect, functional assays have found conflicting results. In vitro studies of mismatch repair found this variant to demonstrate reduced activity, but results from studies assessing mutator effect and MLH1 protein expression were inconsistent (Ellison 2004, Plotz 2006, Takahashi 2007, Wanat 2007, Hardt 2011, Bolz 2012). Additionally, Plotz et al. (2006) did not find this variant to impact interaction with PMS2. Based on currently available evidence, it is unclear whether MLH1 Asn64Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000075426 SCV000218899 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 64 of the MLH1 protein (p.Asn64Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs63750952, ExAC 0.009%). This variant has been reported in individuals affected with Lynch syndrome, endometrial cancer or pancreatic cancer (PMID: 9311737, 21404117, 26552419, 28514183, 28767289) and in two individuals in a single family affected with colorectal cancer where one unaffected individual has this variant (PMID: 16736289). ClinVar contains an entry for this variant (ID: 89947). Experimental studies have shown that this sequence change significantly reduces but does not eliminate mismatch repair activity (PMID: 17510385, 17135187), and partially disrupts MLH1 interaction with PMS2 (PMID: 21404117). 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.
Mendelics RCV000708912 SCV000837994 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000513562 SCV000889392 uncertain significance not provided 2018-05-09 criteria provided, single submitter clinical testing

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