ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2174G>A (p.Arg725His) (rs566928243)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586779 SCV000149382 uncertain significance not provided 2018-11-15 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2174G>A at the cDNA level, p.Arg725His (R725H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been observed in individuals with a personal history of colorectal cancer or colon polyps, two of whom also had a family history of pancreatic cancer (Chao 2008, Kraus 2015, Shirts 2016). This variant was interrogated using several assays, and revealed that although protein expression was reduced, cellular viability and DNA damage response (DDR) signaling was similar to wild type, concluding that this variant was moderately functional (Arora 2017). MLH1 Arg725His was observed at an allele frequency of 0.35% (36/10,138 alleles) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is located in the region of interaction with PMS2, MLH3, and PMS1 (Raevaara 2005, Kansikas 2011, Andersen 2012). In silico analyses analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertain" based on insufficient evidence (Thompson 2014). Based on currently available evidence, it is unclear whether MLH1 Arg725His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance."
Invitae RCV000586779 SCV000166250 benign not provided 2019-03-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115473 SCV000184522 likely benign Hereditary cancer-predisposing syndrome 2017-04-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Conflicting evidence
University of Washington Department of Laboratory Medicine,University of Washington RCV000075568 SCV000266178 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Color RCV000115473 SCV000537527 likely benign Hereditary cancer-predisposing syndrome 2017-05-23 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212549 SCV000592444 uncertain significance not specified criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212549 SCV000601390 uncertain significance not specified 2016-11-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586779 SCV000696150 uncertain significance not provided 2016-12-22 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.2174G>A (p.Arg725His) variant located in the C-terminal domain (via InterPro) causes a missense change involving a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 18/121334 (1/6738), predominantly in the European (Non-Finnish) cohort, 18/66728 (1/3706), which does not exceed the estimated maximal expected allele frequency for a pathogenic MLH1 variant of 1/1407. Multiple publications have cited the variant in affected individuals, however, due to lack of information (ie, no cosegregation and/or co-occurrence data being provided), a pathogenicity cannot be established. The variant of interest was recently reported in a 73 y/o male with MSS (microsatellite stable) colorectal cancer and normal IHC. Tumor sequencing identified the following mutations: APC, p.Gln1367X, p53 p.Arg175His, and SMAD4 p.Gln516X, which could represent driver mutations in other well established genes that could be causative of a non-inherited form of cancer in this individual. In ClinVar, one clinical diagnostic laboratory states that an internal sample had a co-occurrence with a pathogenic MSH6 variant, although the variant is not provided. Therefore, both the published report and the ClinVar evidence seem to point towards an alternate molecular basis of disease in patients with this variant. In addition, multiple clinical diagnostic laboratories cite the variant as "uncertain significance. Therefore, until additional information becomes available, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)-possibly benign.
GeneKor MSA RCV000115473 SCV000822022 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764498 SCV000895569 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing

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