ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.803A>G (p.Glu268Gly) (rs63750650)

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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) RCV000075874 SCV000106889 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
Ambry Genetics RCV000130956 SCV000185871 likely benign Hereditary cancer-predisposing syndrome 2018-12-27 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
Invitae RCV000524319 SCV000253146 benign Hereditary nonpolyposis colorectal neoplasms 2020-11-15 criteria provided, single submitter clinical testing
Counsyl RCV000410902 SCV000488222 benign Lynch syndrome II 2016-02-02 criteria provided, single submitter clinical testing
GeneDx RCV001703977 SCV000513617 likely benign not provided 2019-06-05 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25637381, 26761715, 21404117, 18383312, 17510385, 9611074, 11304573, 25871441, 17192056, 23741719, 22290698)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000434087 SCV000539639 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Insufficient evidence for pathogenicity, ExAC: 0.1% (6/6614) Finnish chromosomes
Color Health, Inc RCV000130956 SCV000684872 likely benign Hereditary cancer-predisposing syndrome 2015-12-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000434087 SCV000919658 likely benign not specified 2020-10-05 criteria provided, single submitter clinical testing Variant summary: MLH1 c.803A>G (p.Glu268Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) 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 0.00025 in 251626 control chromosomes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (0.00025 vs 0.00071), allowing no conclusion about variant significance. c.803A>G has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and also in breast and ovarian cancer (example: Jarhelle_2019, Liu_1998). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrence with other pathogenic variant have been reported (MSH2 c.1552_1553delCA, p.Gln518fs), providing supporting evidence for a benign role (Liu_1998). In in vitro functional MMR activity assays, the variant was found to have >50%-90% of normal activity. Seven other ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=6) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000410902 SCV001136386 benign Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148616 SCV000190331 likely benign Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357445 SCV001552919 likely benign Carcinoma of colon no assertion criteria provided clinical testing The MLH1 p.Glu268Gly variant was identified in 1 of 284 proband chromosomes (frequency: 0.004) from Swedish individuals or families with CRC, cooccurring with MSH2 c.1552_1553del, p.Gln518ValfsX10 (alias del CA at 518), and the proband’s tumour characterized as MSI positive, MLH1 IHC intact but MSH2 IHC deficient (Wahlberg 1999, Liu 1998, Salahshor 2001). Functional assays using minigene assays showed the variant yielded >70% transcripts with exon 10 inclusion; and ESR-dedicated bioinformatics tools showed there was no effect on splicing (Soukarieh 2016). Additional functional analyses using yeast assays/other demonstrated a dominant mutator effect, 79% in vitro MMR activity and 25-75% MLH1 expression (Takahashi 2007). A further bioinformatics algorithm using multivariate analysis assessed the variant to be deleterious with a MAPP-MMR score of 5.2, the optimal MAPP-MMR threshold segregating deleterious and neutral variants being 4.55 (Chao 2008). The variant was also identified in dbSNP (ID: rs63750650) as “other”, ClinVar (classified as benign, reviewed by an expert panel (2013); submitters: benign by InSIGHT, Counsyl; likely benign by Ambry Genetics, Invitae, GeneDx, CSER-CC-NCGL: University of Washington Medical Center; uncertain significance by Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine)), Clinvitae (5X), Insight Colon Cancer Gene Variant Database (21X as Class 1), and Mismatch Repair Genes Variant Database, but was not identified in Genesight-COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, and Insight Hereditary Tumors Database. The variant was identified in control databases in 65 of 277192 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Glu268 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Gly variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 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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