ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586779 SCV000149382 uncertain significance not provided 2021-07-12 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with colorectal cancer or polyps, breast cancer, or endometrial cancer (Chao 2008, Kraus 2015, Shirts 2016, Sung 2017, zdemir); Published functional studies are inconclusive: reduced protein expression, but cellular viability and DNA damage response (DDR) signaling were similar to wild type (Arora 2017); This variant is associated with the following publications: (PMID: 18383312, 26845104, 28961279, 30238922, 25142776, 31159747, 28494185, 12799449, 20533529, 22753075, 22585170, 25503501, 28125075, 26269718, 15184898, 22290698)
Invitae RCV001079417 SCV000166250 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115473 SCV000184522 likely benign Hereditary cancer-predisposing syndrome 2018-05-16 criteria provided, single submitter clinical testing Conflicting evidence;Insufficient or 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 Health, Inc RCV000115473 SCV000537527 likely benign Hereditary cancer-predisposing syndrome 2017-05-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212549 SCV000601390 benign not specified 2020-02-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212549 SCV000696150 uncertain significance not specified 2021-07-12 criteria provided, single submitter clinical testing Variant summary: MLH1 c.2174G>A (p.Arg725His) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251152 control chromosomes. However, the frequency at which the variant is found in the Ashkenazi Jewish population is higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (0.0036 vs 0.00071), suggesting the variant may be a polymorphism found in that population. c.2174G>A has been reported in the literature in individuals affected with colorectal, breast, endometrial and pancreatic cancers, without strong evidence for pathogenicity (eg. Chao_2008, Kraus_2015, Lipkin_2004, Shirts_2016, Abe_2019, Ozdemir_2019, Sung_2017, Tsaousis_2019, Solmaz_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, showing reduced expression, but overall reported the variant to be moderately functional (Arora_2017). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four submitters classified the variant as benign/likely benign while five classified the variant as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.
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
Illumina Clinical Services Laboratory,Illumina RCV001147135 SCV001307917 uncertain significance Lynch syndrome II 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000586779 SCV000592444 uncertain significance not provided no assertion criteria provided clinical testing

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