ClinVar Miner

Submissions for variant NM_001354630.1(MLH1):c.1732-878_1732-877delinsGC (rs35502531)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075382 SCV000106375 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
Ambry Genetics RCV000130907 SCV000185816 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV001080780 SCV000252646 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-08 criteria provided, single submitter clinical testing
Vantari Genetics RCV000130907 SCV000267048 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-25 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121363 SCV000601370 benign not specified 2017-05-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130907 SCV000684775 likely benign Hereditary cancer-predisposing syndrome 2015-07-13 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000018620 SCV000781761 likely benign Lynch syndrome II 2016-11-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000121363 SCV000805957 benign not specified 2017-01-13 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283623 SCV000885702 benign none provided 2020-03-27 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000121363 SCV001158184 benign not specified 2019-06-06 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000075382 SCV001439179 benign Lynch syndrome 2020-09-23 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000018620 SCV001440472 uncertain significance Lynch syndrome II 2019-01-01 criteria provided, single submitter clinical testing
OMIM RCV000018620 SCV000038903 uncertain significance Lynch syndrome II 2010-08-01 no assertion criteria provided literature only
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034542 SCV000043327 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
ITMI RCV000121363 SCV000085544 not provided not specified 2013-09-19 no assertion provided reference population
Pathway Genomics RCV000144600 SCV000189927 likely benign Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000121363 SCV000257068 uncertain significance not specified no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353882 SCV000592423 likely benign Carcinoma of colon no assertion criteria provided clinical testing The p.Lys618Ala variant has been previously reported in the literature. It has been identified in 48/8212 (Freq: 0.006) proband chromosomes from families with colorectal cancer and or other cancer types and in 29/6204 (Freq: 0.005) control chromosomes, increasing the likelihood that this is a polymorphism (Auclair_2006_16395668; Barnetson_2008_18033691; Belvederesi_2006_16724012; Bianchi_2007_17250665; Fearnhead_2004_15520370; Fidalgo_2000_10713887; Gille_2002_12373605; Hampel_2006_16885385; Hedge_2005_16237223; Hudler_2004_15099349; Papp_2007_17569143; Perera_2007_18205192; Pinol_2005_15855432; Rubio-Del-Campo_2007_18325052; Scott_2001_11112663; Steinke_2008_18301448; Syngal_1999_10422993; Ward_2002_12200596; Weber_1997_9288790; Wolf_200515926618; Wijnen_1997_9311737; Tannergard_1995_8521398). Contradictory evidence exists regarding the functional significance of this variant. In vitro studies have demonstrated that the p.Lys618Ala substitution results in an 85% reduction in efficiency of binding to PMS2 and that it was unable to reverse the mutator phenotype in an MLH1 deficient ovarian cancer cell line (Blasi_2006_16982745; Guerrette_1999_10037723). However, Perera et al (2007) demonstrated that the p.Lys618Ala variant did not appear to perturb the ability of MLH1 to heterodimerize with the PMS2 protein. Although, they also showed that the variant protein had a half-life that was significantly decreased compared to the wild-type protein (Perera_2007_18205192), suggesting that this variant may have some functional consequence. There is a significant evidence against the pathogenicity of this variant. Previous studies have identified p.Lys618Ala variant in patients with Microsatelite Stable colorectal carcinomas that expressed MLH1 (Farrington et al., 1998; Liu_1999_10598809; Mauillon et al., 1996; Muller-Koch_2001_11726306; Samowitz et al., 2001; Wolf_2005_15926618). Several studies report this variant in the presence of a second variant which was in some cases pathogenic. For example an out-of-frame splice mutation (a A>G at position –2 in intron 6 of the hMLH1-gene). The splice mutation caused skipping of exon 7 and was shared with a younger sibling who had three consecutive CRCs and gastric cancer, all associated with MSI (Liu_1999_10598809). In this case, the p.Lys618Ala variant did not co-segregate with disease (Tannergard_1995_8521398). Still in another study, the MSH2 protein product was demonstrated to be absent and the MLH1 protein product was present in one affected individual with this variant, increasing the likelihood that the p.Lys618Ala variant is not pathogenic (Pinol_2005_15855432). Steinke et al (2008_18301448) also identified this variant in the presence of a second variant in two individuals, one was a pathogenic stop codon (Syngal_1999_10422993). In summary, based on the above information, this variant is predicted to be benign. Although it is predicted benign we cannot rule out that it may contribute to or modify the clinical features observed in this individual.
True Health Diagnostics RCV000130907 SCV000788018 likely benign Hereditary cancer-predisposing syndrome 2018-01-03 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000034542 SCV001808046 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000121363 SCV001906390 benign not specified no assertion criteria provided clinical testing

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