ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.83C>T (p.Pro28Leu) (rs63750792)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075881 SCV000106897 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics RCV000160552 SCV000213763 pathogenic Hereditary cancer-predisposing syndrome 2018-12-19 criteria provided, single submitter clinical testing The p.P28L pathogenic mutation (also known as c.83C>T), located in coding exon 1 of the MLH1 gene, results from a C to T substitution at nucleotide position 83. The proline at codon 28 is replaced by leucine, an amino acid with similar properties. This mutation has been found in multiple families that meet Amsterdam I or Amsterdam II criteria for Lynch syndrome, or had a personal and family history of an HNPCC-related cancer (Kurzawski G et al. J Med Genet. 2002 Oct;39(10):E65; Raevaara, T et al. Gastroenterology. 2005 Aug;129(2):537-49). In addition, individuals with this mutation have <span style="background-color:initial">concordant <span style="background-color:initial">tumor studies showing <span style="background-color:initial">microsatellite <span style="background-color:initial">instability and/or loss of MLH1 with <span style="background-color:initial">immunohistochemistry <span style="background-color:initial">(<span style="background-color:initial">Raevaara T et al. Gastroenterology<span style="background-color:initial">. 2005 Aug;129(2):537-49; <span style="background-color:initial">Spaepen et al. Familial Cancer, 2006 <span style="background-color:initial">;5(2):179-89<span style="background-color:initial">; <span style="background-color:initial">Mangold et al. J Pathol <span style="background-color:initial">2005 <span style="background-color:initial">Dec;207(4):385-95; <span style="background-color:initial">Lamberti C et al. <span style="background-color:initial">Gut 1999 Jun;44(6):839-43)<span style="background-color:initial">. Multiple functional studies have reported that this mutation causes reduced mismatch repair efficiency compared to the wild-type allele (Raevaara T et al. Gastroenterology<span style="background-color:initial">. 2005 Aug;129(2):537-49; Takahashi M et al. Cancer Res.<span style="background-color:initial"> 2007 May 15;67(10):4595-604). This mutation is in the ATPase domain of MLH1<span style="background-color:initial"> and other functional studies have reported that it disrupts the interaction of the MLH1 protein with PMS2, supporting that it is pathogenic (Hardt K et al. Fam Cancer.<span style="background-color:initial"> 2011 Jun;10(2):273-84; Kondo E et al. Cancer Res. <span style="background-color:initial">2003 Jun 15;63(12):3302-8). <span style="background-color:initial">This alteration has been classified as a class 5 mutation by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000075881 SCV000259722 likely pathogenic Lynch syndrome 2015-08-02 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 28 of the MLH1 protein (p.Pro28Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in the population databases (rs63750792, no frequency), but has been reported in individuals affected with Lynch syndrome, although no segregation data is available (PMID: 9298827, 10323887, 12624141, 16083711, 16451135, 16736289, 17510385, 21404117). ClinVar has an entry for this variant (RCV000160552). Experimental studies have shown that this missense change abrogates the mismatch repair function of the MLH1 protein, which is unable to rescue the functional phenotype presented by MLH1 null cells (PMID: 10082584, 16083711, 17210669, 17510385). For these reasons, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000075881 SCV000696183 pathogenic Lynch syndrome 2016-06-16 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.83C>T (p.Pro28Leu) 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 is absent in 121156 control chromosomes. This variant has been reported in multiple affected individuals and functional studies showed that variant causes deficient MMR activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000075881 SCV000914313 pathogenic Lynch syndrome 2019-01-30 criteria provided, single submitter research
Color Health, Inc RCV000160552 SCV001351149 pathogenic Hereditary cancer-predisposing syndrome 2020-04-29 criteria provided, single submitter clinical testing
Invitae RCV001380943 SCV001579171 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 28 of the MLH1 protein (p.Pro28Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Lynch syndrome (PMID: 16083711, 16736289). ClinVar contains an entry for this variant (Variation ID: 90388). Experimental studies have shown that this variant affects MLH1 protein function (PMID: 10082584, 17210669, 17510385). For these reasons, this variant has been classified as Pathogenic.

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