Submissions for variant NM_000249.4(MLH1):c.884+16A>G

gnomAD frequency: 0.00011  dbSNP: rs377598055

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160557	SCV000211135	benign	not specified	2014-07-22	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.
Counsyl	RCV000411740	SCV000489196	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2016-08-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579749	SCV000684878	likely benign	Hereditary cancer-predisposing syndrome	2015-04-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589525	SCV000696186	uncertain significance	not provided	2016-01-07	criteria provided, single submitter	clinical testing	Variant summary: This c.884+16A>G variant affects a non-conserved nucleotide, resulting in intronic change at a position not widely known to affect normal splicing. 4/5 splice-site tools via Alamut predict that this variant does not affect normal splicing. ESEfinder also predicts the variant not to affect any ESE binding sites. This variant was found in 22/121388 chromosomes from the broad and large populations of ExAC at a frequency of 0.0001812. It was mainly found in the European Non-Finnish sub-population where its allele frequency is 0.0003 (20/66728 chromosomes), which, albeit is lower than the maximal expected allele frequency in this gene (0.0007105), suggests that it might be a rare polymorphism in this population. To our knowledge, the variant has not been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. One clinical lab has classified this variant as benign. Taken together, this variant has currently been classified as VUS-possibly benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000589525	SCV002009352	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002053926	SCV002393471	benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-02	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000160557	SCV002552445	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000579749	SCV002683894	likely benign	Hereditary cancer-predisposing syndrome	2015-10-22	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149976	SCV003838863	likely benign	Breast and/or ovarian cancer	2023-04-18	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000589525	SCV001808104	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000160557	SCV001921294	benign	not specified		no assertion criteria provided	clinical testing