Submissions for variant NM_000249.4(MLH1):c.303T>G (p.Gly101=)

gnomAD frequency: 0.00002  dbSNP: rs4647220

Total submissions: 17

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	2024-02-01	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	This alteration is classified as 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.
Illumina Laboratory Services, Illumina	RCV001094909	SCV000443325	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	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 Diagnostics, LLC DBA Color Health	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	RCV000121356	SCV000888182	benign	not specified	2021-12-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587630	SCV002505982	likely benign	not provided	2022-02-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149738	SCV003838858	benign	Breast and/or ovarian cancer	2021-09-14	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001094909	SCV004015871	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121356	SCV004024889	likely benign	not specified	2023-08-15	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.
Clinical Genetics, Academic Medical Center	RCV000121356	SCV001919882	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000587630	SCV001963542	likely benign	not provided		no assertion criteria provided	clinical testing