ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1487C>G (p.Pro496Arg) (rs63750226)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221321 SCV000273311 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000221321 SCV000684749 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing
Counsyl RCV000409591 SCV000488536 uncertain significance Lynch syndrome II 2016-04-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764493 SCV000895564 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000483364 SCV000565156 uncertain significance not provided 2015-02-16 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1487C>G at the cDNA level, p.Pro496Arg (P496R) at the protein level, and results in the change of a Proline to an Arginine (CCC>CGC). This variant has been observed in at least one individual with endometrial cancer; tumor testing revealed microsatellite stability and immunohistochemistry reported presence of MLH1 protein and absence of MSH2 protein (Bianchi 2007). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertain, due to insufficient evidence (Thompson 2014). MLH1 Pro496Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Proline and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Pro496Arg occurs at a position that is highly conserved among mammals and is located within a region that interacts with EX01 (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MLH1 Pro496Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075225 SCV000106217 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000627722 SCV000254351 uncertain significance Hereditary nonpolyposis colon cancer 2018-07-17 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 496 of the MLH1 protein (p.Pro496Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs63750226, ExAC 0.03%). This variant has been reported in the literature in an individual affected with endometrial cancer (PMID: 17250665). ClinVar contains an entry for this variant (Variation ID: 89751). 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 C0"). 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.

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