ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2252A>G (p.Lys751Arg) (rs140195825)

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Total submissions: 11
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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 In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
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
Invitae RCV001082066 SCV000254368 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000409128 SCV000489128 likely benign Lynch syndrome II 2016-08-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759084 SCV000888180 likely benign not provided 2019-03-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115476 SCV000903065 benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
Mendelics RCV000409128 SCV001136439 likely benign Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000409128 SCV001307918 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 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.

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