ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.793C>T (p.Arg265Cys) (rs63751194)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075872 SCV000106886 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes aberrant splicing leading to truncated protein: full inactivation of variant allele.
Invitae RCV000524317 SCV000262499 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 265 of the MLH1 protein (p.Arg265Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with colorectal cancer or Lynch syndrome (PMID: 12386821, 15713769, 19419416, 20587412, 20864636), and has been shown to co-segregate with disease in multiple affected families (PMID: 19419416, 20587412). ClinVar contains an entry for this variant (Variation ID: 29654). While the effect of this variant on mismatch repair (MMR) activity is variable across different functional studies (PMID: 11555625, 11781295, 17135187, 17510385), experimental in vivo splicing studies have shown that this variant affects mRNA splicing, causing protein truncation in assays using patient-derived mRNA (PMID: 12386821, 15713769, 18561205). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000220712 SCV000276047 pathogenic Hereditary cancer-predisposing syndrome 2018-05-03 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Good segregation with disease (lod 1.5-3 = 5-9 meioses);Functionally-validated splicing mutation
GeneDx RCV000034802 SCV000279078 pathogenic not provided 2018-07-06 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.793C>T at the cDNA level, p.Arg265Cys (R265C) at the protein level. This variant disrupts a nearby natural splice acceptor site and causes abnormal splicing. Although the nucleotide substitution results in the change of an Arginine to a Cysteine at codon 265, the primary defect is determined to be one of splicing rather than a resulting missense variant. MLH1 c.793C>T has been found to cause aberrant splicing and reduce mRNA and protein expression as well as protein stability and binding of MLH1 to PMS2 (Yuen 2002, Casey 2005, Perera 2008, Perera 2010, Andersen 2012, Fan 2012, Soukarieh 2016). This variant has been observed in many individuals with personal and/or family histories of colon cancer, many of which met Amsterdam or Bethesda Lynch Syndrome criteria, whose corresponding tumors were often microsatellite unstable and/or had abnormal protein staining on immunohistochemistry (Wahlberg 1999, Hutter 2002, Yuen 2002, Hendriks 2003, Mangold 2005, Wolf 2005, Lagerstedt Robinson 2007, Berginc 2009, Choi 2009, Tang 2009, Chang 2010, Sjursen 2010, Woods 2010, Bonadona 2011, Hardt 2011, Fan 2012, Liu 2014, Guindalini 2015, Win 2015). Tang et al. (2009) reported this variant to co-segregate with cancer in thirteen unrelated families from Taiwan and determined that this variant was derived from two distinct haplotypes, suggesting a founder effect. Lastly, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic, causing aberrant splicing and leading to a truncated protein (Thompson 2014). Based on currently available evidence, we consider this variant to be pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075872 SCV000592378 pathogenic Lynch syndrome 2014-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000022502 SCV000677736 pathogenic Lynch syndrome II 2017-03-02 criteria provided, single submitter clinical testing
Color RCV000220712 SCV000684870 pathogenic Hereditary cancer-predisposing syndrome 2017-04-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000075872 SCV000696181 pathogenic Lynch syndrome 2016-04-21 criteria provided, single submitter clinical testing Variant summary: Variant affects a conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a medium size and polar Cysteine (C). 4/4 in silico tools predict the variant to be disease causing (SNPs&GO was not capture due to low reliability index). The variant is absent from the large and broad cohorts of the ExAC project while it was observed in several HNPCC patients indicating pathogenicity. Moreover, the variant is considered to be a founder mutation in populations of Chinese/Taiwanese origin. Functional studies report the variant to result in exon skipping and a partial MMR defect which in combination likely result in a pathogenic impact. Furthermore, a clinical laboratory and databases cite variant as Pathogenic. Considering all evidence, the variant was classified as a Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000075872 SCV000731294 pathogenic Lynch syndrome 2016-11-17 criteria provided, single submitter clinical testing The p.Arg265Cys variant in MLH1 is absent from large population studies but has been reported in >30 individuals with Lynch Syndrome (Casey 2005, Hardt 2011, Ta ng 2009, InSiGHT database: hp). It segregated with disease in at least 12 family members (Hardt 2011, Tang 2009). Functional studies using patient mRNA showed that the variant leads to ex on skipping and protein truncation (Casey 2005). Additionally, this variant has been classified as pathogenic on Sept 5, 2013 by the ClinGen-approved InSiGHT pa nel (ClinVar SCV000106886.2). In summary, this variant meets criteria to be clas sified as pathogenic for Lynch Syndrome in an autosomal dominant manner based up on segregation studies and the impact of the variant on the protein.
3DMed Clinical Laboratory Inc RCV000677879 SCV000804040 pathogenic Carcinoma of colon 2018-02-10 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000022502 SCV001429381 pathogenic Lynch syndrome II 2019-05-06 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034802 SCV000043333 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
OMIM RCV000022502 SCV000043791 pathogenic Lynch syndrome II 2009-04-01 no assertion criteria provided literature only
Ding PR Lab,Sun Yat-sen University Cancer Center RCV001093673 SCV001250854 pathogenic Lynch syndrome I no assertion criteria provided clinical testing

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