ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2041G>A (p.Ala681Thr) (rs63750217)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075495 SCV000106491 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV000524270 SCV000218745 pathogenic Hereditary nonpolyposis colon cancer 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 681 of the MLH1 protein (p.Ala681Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with colorectal cancer (PMID: 16083711, 23354017), and several families with Lynch syndrome (PMID: 12362047, 18033691, 8880570, 21642682, 22736432). In two of the Lynch syndrome families, this variant was reported to segregate with disease in 16 affected family members (PMID: 18033691, 8880570). In those patients' tumors that were tested, there was high microsatellite instability and/or absence of MLH1 protein expression by immunohistochemistry (PMID: 18033691, 23403630, 16083711). This variant is also known as 2062G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 17099). This variant is located within the PMS2 interaction domain of MLH1 protein (PMID: 21404117). Although there are conflicting results, experimental studies have shown that this missense change disrupts MLH1 protein function (PMID: 9697702, 17510385, 21404117, 10037723, 12810663, 15864295, 16083711, 25477341). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000213700 SCV000275301 pathogenic Hereditary cancer-predisposing syndrome 2019-02-07 criteria provided, single submitter clinical testing Good segregation with disease (lod 1.5-3 = 5-9 meioses);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Counsyl RCV000018632 SCV000488784 pathogenic Lynch syndrome II 2016-06-16 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075495 SCV000592438 likely pathogenic Lynch syndrome 2016-05-27 criteria provided, single submitter clinical testing
GeneDx RCV000519240 SCV000616784 pathogenic not provided 2019-01-04 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.2041G>A at the cDNA level, p.Ala681Thr (A681T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). This variant has been observed in multiple individuals with colorectal cancer, meeting either Amsterdam criteria or Bethesda guidelines (Froggatt 1996, Jakubowska 2001, Giraldo 2005, Mangold 2005, Barnetson 2006, Kurzawski 2006, Sheng 2006, de Leon 2007, Pedroni 2007, Barnetson 2008, Alvarez 2010, Jasperson 2010, Hardt 2011, Rodriguez-Solez 2013). Several of these individuals were identified to have tumors that were MSI-high and had absent MLH1 staining (Barnetson 2006, Sheng 2006, Pedroni 2007, Jasperson 2010, Hardt 2011, Rodriguez-Soler 2013). This variant was identified to segregate with cancer in 16 affected relatives in two families (Froggatt 1996, Barnetson 2008). Functional studies for this variant have shown similar in vitro MMR activity compared to wild type, reduced MLH1 expression, reduced binding with PMS2, and significantly reduced binding with MRE11 (Guerrette 1999, Vo 2005, Takahashi 2007, Hardt 2011, Drost 2018), MLH1 Ala681Thr was not observed in large population cohorts (Lek 2016). MLH1 Ala681Thr is located in the PMS2/MLH3/PMS1 interaction region (Raevaara 2005, Kansikas 2010, Andersen 2012). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). Based on currently available evidence, we consider this variant to be pathogenic.
Color RCV000213700 SCV000689855 pathogenic Hereditary cancer-predisposing syndrome 2020-04-22 criteria provided, single submitter clinical testing
GeneKor MSA RCV000519240 SCV000821735 likely pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This sequence change replaces Alanine with Threonine at codon 681 of the MLH1 protein (p.Ala681Thr). The alanine residue is weakly conserved among species and is located in a domain of the protein that is known to be functionally important. There is a small physicochemical difference between Alanine and Threonine (Grantham Score 58). This sequence change has been reported in the literature and is not present in population databases (rs63750217). This variant was reported in several individuals affected with colorectal cancer and Lynch syndrome (PMID: 16083711, 23354017, 18033691, 8880570). The mutation database ClinVar contains entries for this variant (Variation ID: 17099).Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. Moreover, experimental studies have shown that this missense change disrupts MLH1 protein function (PMID: 9697702, 17510385, 21404117).
Fulgent Genetics,Fulgent Genetics RCV000763105 SCV000893647 pathogenic Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000075495 SCV000914326 pathogenic Lynch syndrome 2019-01-30 criteria provided, single submitter research
OMIM RCV000018632 SCV000038915 pathogenic Lynch syndrome II 2006-01-01 no assertion criteria provided literature only
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202172 SCV000257082 uncertain significance not specified no assertion criteria provided research
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000018632 SCV000484931 likely pathogenic Lynch syndrome II no assertion criteria provided clinical testing

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