ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1808C>G (p.Pro603Arg) (rs63750876)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075369 SCV000106364 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
Ambry Genetics RCV000130908 SCV000185817 likely benign Hereditary cancer-predisposing syndrome 2018-12-19 criteria provided, single submitter clinical testing Does not segregate with disease in family study (genes with incomplete penetrance);Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
GeneDx RCV000034541 SCV000211144 likely benign not provided 2021-03-04 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 11726306, 17510385, 21404117, 23047549, 23741719, 19117025, 22736432, 24362816, 22949387, 22703879, 25871441, 18561205, 22290698, 31784484)
Invitae RCV001082925 SCV000218694 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130908 SCV000537430 likely benign Hereditary cancer-predisposing syndrome 2015-03-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000417382 SCV000601368 likely benign not specified 2017-01-17 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034541 SCV000805956 uncertain significance not provided 2018-01-04 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034541 SCV000889389 benign not provided 2018-04-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000417382 SCV000919654 likely benign not specified 2017-12-26 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1808C>G (p.Pro603Arg) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However in vitro and ex vivo functional studies indicated that this variant has no effect on splicing and protein function as assessed by the DNE (Dominant Negative Mutator effect) assay (Tournier 2008, Takahashi 2007). The dominant negative mutator effect (DNE) in yeast is based on the observation that wild-type (wt) human MLH1 interferes with the yeast MMR system and increases the mutation rate of test substrates. This variant was found in 45/277050 control chromosomes, predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.003055 (31/10148). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105), suggesting this is likely a benign polymorphism found primarily in the populations of Ashkenazi Jewish origin. This variant was reported in patients with HNPCC (Hardt 2011, Tournier 2008) without strong evidence for causality. Lastly, at-least one non-published report on a co-occurrence of this variant with the complete deletion of the MLH1 gene has been reported in the UMD locus specific database. However, this observation has not been independently evaluated by other laboratories to include ours. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign.
Mendelics RCV000987184 SCV001136423 likely benign Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000987184 SCV001310414 uncertain significance Lynch syndrome II 2017-04-28 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.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034541 SCV000043326 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356052 SCV001551110 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The MLH1 p.Pro603Arg variant was identified in 6 of 4996 proband chromosomes (frequency: 0.005) from individuals or families with lynch syndrome and ovarian cancer (Pal 2012, South 2009, Hardt 2011, Borras 2012, Tournier 2008). The variant was identified in dbSNP (rs63750876) as “with uncertain significance allele”, ClinVar (classified as likely benign by GeneDx, Ambry Genetics, Integrated Genetics, Color and 2 other submitters, uncertain significance by Prevention Genetics and NIH and benign by Invitae and Quest Diagnostics) and UMD-LSDB (observed 4x). The variant was identified in control databases in 44 of 282,716 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 29 of 10,366 chromosomes (freq: 0.003 increasing the likelihood this could be a low frequency benign variant), Other in 5 of 7218 chromosomes (freq: 0.0007), European in 8 of 129,068 chromosomes (freq: 0.00006), Latino in 2 of 35,438 chromosomes (freq: 0.00006), while the variant was not observed in the African, East Asian, Finnish, and South Asian populations. Expression of the variant in yeast and human cells had no demonstrated effect on MLH1 protein levels, MMR activity and splicing (Norras 2012, Hardt 2011, Tournier 2008, Takahashi 2007). The p.Pro603 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.