ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.776T>C (p.Leu259Ser) (rs56250509)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160527 SCV000211095 uncertain significance not provided 2017-12-15 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.776T>C at the cDNA level, p.Leu259Ser (L259S) at the protein level, and results in the change of a Leucine to a Serine (TTA>TCA). A yeast two-hybrid assay demonstrated that MLH1 Leu259Ser retains the ability to interact with PMS2, suggesting that this variant does not impact PMS2 binding (Wang 2012). MLH1 Leu259Ser was observed at an allele frequency of 0.03% (5/17,244) in individuals of East Asian ancestry in large population cohorts (Lek 2016). Since Leucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Leu259Ser is located in 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 Leu259Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000411294 SCV000488045 uncertain significance Lynch syndrome II 2015-12-18 criteria provided, single submitter clinical testing
Invitae RCV000525411 SCV000625191 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-22 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 259 of the MLH1 protein (p.Leu259Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs56250509, ExAC 0.06%). This variant has been reported in an individual in the Universal Mutation Database (PMID: 23729658). However, in that individual a pathogenic allele was also identified in MLH1, which suggests that this c.776T>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 182519). An experimental study has shown that this missense change does not affect the interaction of the MLH1 protein with PMS2 (PMID: 22252508). 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.
Ambry Genetics RCV000562377 SCV000669540 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000562377 SCV000684863 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-13 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000160527 SCV000805981 uncertain significance not provided 2018-01-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780420 SCV000917660 uncertain significance not specified 2018-08-13 criteria provided, single submitter clinical testing Variant summary: MLH1 c.776T>C (p.Leu259Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like domain 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 2e-05 in 245718 control chromosomes (gnomAD), predominantly at a frequency of 0.00029 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.776T>C has been reported in the literature in a CML cell line (Hangaishi_1997). This report does not provide an unequivocal conclusion about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MLH1 c.1989+1G>T (2X)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160527 SCV001134322 uncertain significance not provided 2019-08-13 criteria provided, single submitter clinical testing

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