ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.303T>G (p.Gly101=) (rs4647220)

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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) RCV000075626 SCV000106628 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Synonymous substitution with no effect on splicing & MAF 0.01-1%
Invitae RCV001084168 SCV000166253 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000121356 SCV000211152 benign not specified 2014-08-15 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000160567 SCV000212812 benign Hereditary cancer-predisposing syndrome 2019-10-23 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign);RNA Studies
Illumina Clinical Services Laboratory,Illumina RCV001094909 SCV000443325 likely benign Lynch syndrome II 2019-02-22 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genetic Services Laboratory, University of Chicago RCV000121356 SCV000595799 likely benign not specified 2016-06-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000160567 SCV000684815 benign Hereditary cancer-predisposing syndrome 2015-04-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587630 SCV000696159 benign not provided 2016-05-20 criteria provided, single submitter clinical testing Variant summary: The c.303T>G (p.Gly101=) in MLH1 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing which was supported by a RNA-based functional assay by Thompson et al (2012). The variant is present in the control population dataset of ExAC at frequency of 0.0027 (331/121138) predominantly in individuals of South Asian descent (0.02; 329/16482 chrs) including 5 homozygous occurrences, suggesting that it is a polymorphism mainly found in South Asian population. The variant of interest been reported in affected individuals in whom either another known pathogenic variant was identified (Internal LCA data) or ICH results pointed out mutation(s) in other MMR genes (Mangold, 2007). In addition, the variant is cited as Benign/Likely Benign by reputable databases/clinical laboratories. Taking together, the variant is classified as Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587630 SCV000888182 benign not provided 2017-08-31 criteria provided, single submitter clinical testing
ITMI RCV000121356 SCV000085535 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075626 SCV000592347 benign Lynch syndrome no assertion criteria provided clinical testing The MLH1 p.Gly101Gly was identified in 1 of 20 proband chromosomes (frequency: 0.05) from individuals with Muir-Torre syndrome (Mangold 2007). The variant was also identified in dbSNP (ID: rs4647220) “With other allele”, in the 1000 Genomes Project in 32 of 5000 chromosomes (frequency: 0.0064) and in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 336 of 16482 chromosomes (frequency: 0.02) (or 329 individuals and 5 homozygous individuals) from a population of South Asian individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in Clinvitae database (2x), “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database (2X), the ClinVar database (classified as a likely benign by an expert panel), and UMD (1X as an unknown variant). The p.Gly101Gly variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence, 4th base from the 5' splice region, and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing leading to the loss of a predicted splice site at a non-consensus splice site location; we cannot eliminate the possibility that an exon splice enhancer was modified and may lead to abnormal splicing or creation of a cryptic splice site however this information is not predictive enough to assume pathogenicity. Thompson et al. (2013) assessed MMR (mismatch repair) variants using multifactorial analysis, prior probabilities and likelihood ratios, as well as in vitro splicing assays and found the variant to be Class 3, uncertain significance, and having wildtype splicing. The identification of this variant in an individual with a co-occurring pathogenic variant (MSH2, c.1-?_366+?del) from our laboratory increases the likelihood this variant does not have clinical significance. In summary, based on the above information, this variant is classified as benign.

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