ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1040C>A (p.Thr347Asn) (rs201541505)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115449 SCV000212876 benign Hereditary cancer-predisposing syndrome 2014-12-13 criteria provided, single submitter clinical testing
Color RCV000115449 SCV000910763 likely benign Hereditary cancer-predisposing syndrome 2016-07-14 criteria provided, single submitter clinical testing
GeneDx RCV000587202 SCV000149358 uncertain significance not provided 2018-03-17 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1040C>A at the cDNA level, p.Thr347Asn (T347N) at the protein level, and results in the change of a Threonine to an Asparagine (ACT>AAT). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as benign based on a multifactorial model that incorporates in silico models and segregation within families; however, this data is not available for independent review (Thompson 2013, Thompson 2014). MLH1 Thr347Asn was observed at an allele frequency of 0.013% (14/101,232) in individuals of European ancestry in large population cohorts (Lek 2016). MLH1 Thr347Asn is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether MLH1 Thr347Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000212529 SCV000696093 likely benign not specified 2019-04-18 criteria provided, single submitter clinical testing MLH1 c.1040C>A (p.Thr347Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.3e-05 in 206178 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (7.3e-05 vs 0.00071), allowing no conclusion about variant significance. c.1040C>A has been reported in the literature in at-least one proband affected with colorectal cancer (Thompson_2013). This report(s) does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Additionally, it was reported in a patient with sporadic etiology for colorectal cancer as evidenced by BRAF mutation positivity, high MSI, and a negative MLH1 and PMS2 staining by IHC (van der Klift_2016). BRAF mutation and MLH1 promoter hypermethylation have been reported as strong predictors of a negative germline MMR mutational status (Parsons_2012, PMID 22368298). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Additionally, one submission indicates the variant co-occurred with a pathogenic PMS2 variant (variant not indicated). In addition, an expert panel submitter, InSiGHT, and another submitter (evaluation before 2014) have classified the variant as benign. Therefore, based on the evidence outlined above, the variant was classified as likely benign.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075098 SCV000106090 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
Invitae RCV000524221 SCV000153962 uncertain significance Hereditary nonpolyposis colon cancer 2018-06-19 criteria provided, single submitter clinical testing This sequence change replaces threonine with asparagine at codon 347 of the MLH1 protein (p.Thr347Asn). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and asparagine. This variant is present in population databases (rs201541505, ExAC 0.02%). This variant has been reported in individuals in the Universal Mutation Database (PMID: 23729658) and the Leiden Open-source Variation Database (PMID: 21520333). Additionally, this variant has been observed in the Invitae database in an individual with a family history of breast and colon cancer. However, a pathogenic allele was identified in the PMS2 gene, which suggests that this c.1040C>A substitution in MLH1 was not the primary cause of disease in that individual. ClinVar contains an entry for this variant (Variation ID: 89629). Based on a multifactorial likelihood algorithm using genetic and in silico data, this variant has been determined to have a low probability of being pathogenic (PMID: 22949379). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212529 SCV000539652 uncertain significance not specified 2016-12-14 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is in the second base of exon 12 (of 19 exons). This variant is present in ExAC and gnomAD at a MaxMAF of 0.01% (15 alleles). It is classified in ClinVar as Benign by Ambry and an expert panel (InSiGHT - 3 stars) and as VUS by Invitae and GeneDx. It has not been reported in affected individuals but was seen in the Invitae database in a patient who had another PMS2 variant that was likely to explain disease.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212529 SCV000601343 uncertain significance not specified 2017-05-04 criteria provided, single submitter clinical testing

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