Submissions for variant NM_000249.4(MLH1):c.30G>T (p.Arg10=)

gnomAD frequency: 0.00001  dbSNP: rs876660759

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001354490	SCV000518369	likely benign	not provided	2020-02-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566157	SCV000662042	likely benign	Hereditary cancer-predisposing syndrome	2016-03-31	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.
Color Diagnostics, LLC DBA Color Health	RCV000566157	SCV000689877	likely benign	Hereditary cancer-predisposing syndrome	2017-09-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000443088	SCV000696157	likely benign	not specified	2019-08-29	criteria provided, single submitter	clinical testing
Invitae	RCV000630358	SCV000751314	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996042	SCV004835213	likely benign	Lynch syndrome	2023-10-23	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354490	SCV001549119	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MLH1 p.Arg10= variant was not identified in the literature nor was it identified in the GeneInsight-COGR, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors database. The variant was identified in dbSNP (ID: rs876660759) as "With Likely benign allele", ClinVar (classified as likely benign by GeneDx, Ambry Genetics, Color Genomics, Invitae; as uncertain significance by Integrated Genetics/Laboratory Corporation of America), and Clinvitae databases. The variant was identified in control databases in 2 of 277228 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24038 chromosomes (freq: 0.00004), European in 1 of 126712 chromosomes (freq: 0.00002), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Arg10= 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 and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.