ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.887T>C (p.Leu296Ser) (rs63750547)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222772 SCV000276858 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000588023 SCV000616782 uncertain significance not provided 2017-08-09 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.887T>C at the cDNA level, p.Leu296Ser (L296S) at the protein level, and results in the change of a Leucine to a Serine (TTA>TCA). This variant has been reported in at least one individual with early-onset breast cancer (Rummel 2017). MLH1 Leu296Ser was not observed at a significant frequency in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Leucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Leu296Ser occurs at a position that is conserved across species and is located in the N-terminal ATPase domain (Andersen 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Leu296Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000527338 SCV000625205 uncertain significance Hereditary nonpolyposis colon cancer 2018-06-21 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 296 of the MLH1 protein (p.Leu296Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs63750547, ExAC 0.001%). This variant has been reported in an individual affected with breast cancer (PMID: 28503720). ClinVar contains an entry for this variant (Variation ID: 232668). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Integrated Genetics/Laboratory Corporation of America RCV000588023 SCV000696188 uncertain significance not provided 2016-04-18 criteria provided, single submitter clinical testing Variant summary: The c.887T>C variant involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a pathogenic outcome . The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0008% which does not exceed the maximal expected allele frequency for a pathogenic variant in MLH1 (0.071%). A different variant at the same nucleotide (c.887T>G) causing a nonsense mutation has been reported in association with Lynch Syndrome, however the variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical 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 was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Counsyl RCV000663054 SCV000786104 uncertain significance Lynch syndrome II 2018-02-28 criteria provided, single submitter clinical testing
Color RCV000222772 SCV000905470 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-24 criteria provided, single submitter clinical testing

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