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

gnomAD frequency: 0.00004  dbSNP: rs140195825

Total submissions: 17

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
Invitae	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
PreventionGenetics, part of Exact Sciences	RCV003925033	SCV004738149	likely benign	MLH1-related disorder	2019-09-28	criteria provided, single submitter	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).
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).
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.