ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2239C>T (p.Pro747Ser) (rs587779958)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586644 SCV000149384 uncertain significance not provided 2017-11-06 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2239C>T at the cDNA level, p.Pro747Ser (P747S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). This variant was observed in at least one individual who underwent hereditary cancer panel testing (Yorczyk 2015). MLH1 Pro747Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Pro747Ser occurs at a position that is conserved across species and is not located in a known functional domain. 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 Pro747Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115475 SCV000215265 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000535352 SCV000625136 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 747 of the MLH1 protein (p.Pro747Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs587779958, ExAC 0.01%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 127622). 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 tolerated, 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 RCV000586644 SCV000696153 uncertain significance not provided 2016-11-25 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.2239C>T (p.Pro747Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121356 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). This variant has been reported in one patient without clinical information (Yorczyk_2015). One internal sample carries the variant of interest and BARD1 c.1690C>T/p.Gln564X (pathogenic). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional information becomes available.

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