ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.2252A>G (p.Lys751Arg)

gnomAD frequency: 0.00004  dbSNP: rs140195825
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075586 SCV000106585 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
GeneDx RCV000759084 SCV000149385 likely benign not provided 2020-07-16 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 31697235, 11112663, 11879922, 18383312, 11139242, 23047549, 16451135, 24055113, 16338176, 22949387, 17594722, 25637381, 18033691, 24802709, 17210669, 17510385, 9234704)
Ambry Genetics RCV000115476 SCV000185214 likely benign Hereditary cancer-predisposing syndrome 2019-03-27 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
CSER _CC_NCGL, University of Washington RCV000148620 SCV000190335 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Labcorp Genetics (formerly Invitae), Labcorp RCV001082066 SCV000254368 benign Hereditary nonpolyposis colorectal neoplasms 2024-02-01 criteria provided, single submitter clinical testing
Counsyl RCV000409128 SCV000489128 likely benign Colorectal cancer, hereditary nonpolyposis, type 2 2016-08-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759084 SCV000888180 likely benign not provided 2021-07-20 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115476 SCV000903065 benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
Mendelics RCV000409128 SCV001136439 likely benign Colorectal cancer, hereditary nonpolyposis, type 2 2019-05-28 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000409128 SCV001307918 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 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.
Fulgent Genetics, Fulgent Genetics RCV002498364 SCV002808116 likely benign Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2 2021-12-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003235033 SCV003934377 likely benign not specified 2023-05-18 criteria provided, single submitter clinical testing Variant summary: MLH1 c.2252A>G (p.Lys751Arg) results in a conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251302 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MLH1 causing Lynch Syndrome (7.6e-05 vs 0.00071), allowing no conclusion about variant significance. c.2252A>G has been reported in the literature in individuals affected epithelial ovarian cancer or unspecified cancers (Pal_2012, Li_2020). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At least three functional studies showed this variant has no effect on protein function (Ou_2007, Wanat_2007, Houlleberghs_2020). The following publications have been ascertained in the context of this evaluation (PMID: 31784484, 31391288, 17594722, 23047549, 17510385, 17210669). Nine ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=1) and likely benign (n=6) and benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Myriad Genetics, Inc. RCV000409128 SCV004018210 benign Colorectal cancer, hereditary nonpolyposis, type 2 2023-03-16 criteria provided, single submitter clinical testing This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003492414 SCV004240753 likely benign Breast and/or ovarian cancer 2022-11-29 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV003235033 SCV004848029 likely benign not specified 2017-01-13 criteria provided, single submitter clinical testing MLH1 c.2252A>G: Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in HGMD in 9 papers with comments suggesting benign-VUS. It is classified in ClinVar with 3 stars as Likely benign by InSiGHT (expert panel), GeneDx, Ambry, Invitae, and as VUS by CSER_CC_NCGL. 6 mammals and 2 non-mammals have an Arg at this position. It has a Max MAF in ExAC of 0.01% (9 alleles) and 0.01% in gnomAD (17 alleles).
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000115476 SCV005415581 likely benign Hereditary cancer-predisposing syndrome 2024-09-16 criteria provided, single submitter clinical testing The missense variant NM_000249.4(MLH1):c.2252A>G (p.Lys751Arg) has been reported to ClinVar as Likely benign with a status of (3 stars) reviewed by expert panel (Variation ID 90100 as of 2024-08-01). There is a small physicochemical difference between lysine and arginine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene MLH1 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 1.08. The p.Lys751Arg missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The arginine residue at codon 751 of MLH1 is present in Squirrel monkey and 5 other mammalian species. For these reasons, this variant has been classified as Likely Benign.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355426 SCV001550308 likely benign Carcinoma of colon no assertion criteria provided clinical testing The MLH1 p.Lys751Arg variant was identified in 3 of 1906 proband chromosomes (frequency: 0.00157) from individuals or families with colorectal cancer and was present in 1 of 2100 control chromosomes (frequency: 0.0005) from healthy individuals (Bameston 2008, Jakubowska 2001). The variant was also identified in the following databases: dbSNP (ID: rs140195825) as With Uncertain significance allele, ClinVar (classified as benign by Invitae; classified as likely benign by InSight, GeneDx, Ambry genetics, Counsyl), Clinvitae (classified as benign and likely benign by ClinVar), UMD-LSDB (3X as neutral), Insight Colon Cancer Gene Variant Database (Class2), and the Mismatch Repair Genes Variant Database. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, or Insight Hereditary Tumors Databases. The variant was identified in control databases in 20 of 277026 chromosomes at a frequency of 0.000072 (Genome Aggregation Consortium Feb 27, 2017). The variant was examined in yeast and in vitro MMR assays by Takahashi (2007) and had positive dominant mutator effect with In vitro MMR activity 66.6% compared to 0% in MLH1 deficient cell line. Functional assay by Wanat (2007) was done on the corresponding yeast allele K764R (human K751R) which displayed a lower mutation rate in the SK1 background (51.9-fold). The data suggested the presence of a background-specific difference for K764R that could be a determinant of pathogenicity in humans. The p.Lys751 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences RCV003925033 SCV004738149 likely benign MLH1-related disorder 2019-09-28 no assertion criteria provided clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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