Submissions for variant NM_000249.4(MLH1):c.1039-6dup

dbSNP: rs1553650466

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000128968	SCV000172851	benign	Hereditary cancer-predisposing syndrome	2014-11-18	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233923	SCV000283996	benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV001719899	SCV000729361	benign	not provided	2018-06-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128968	SCV001345272	likely benign	Hereditary cancer-predisposing syndrome	2019-05-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798432	SCV002042066	likely benign	Breast and/or ovarian cancer	2020-06-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128968	SCV002528610	likely benign	Hereditary cancer-predisposing syndrome	2021-06-07	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267868	SCV002552487	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355193	SCV001550007	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MLH1 c.1039-6dupA variant was identified in dbSNP (ID: rs535965616) as “Benign ,Likely benign, Uncertain significance allele”, Clinvitae database (as Benign), ClinVar database (as Benign, by GeneDx, Ambry and Invitae), the 1000 Genomes Project in 239 of 5008 chromosomes (frequency: 0.047), the Exome Aggregation Consortium database (August 8, 2016) in 1441 (49 homozygous) of 43560 chromosomes (frequency: 0.033) in the following populations: African in 282 of 3072 chromosomes (frequency: 0.091), European in 838 of 21102 chromosomes (frequency: 0.039), Finnish in 75 of 2195 chromosomes (frequency: 0.034), East Asian in 80 of 2738 chromosomes (frequency: 0.029), other in 10 of 354 chromosomes (frequency: 0.028), Latino in 60 of 3678 chromosomes (frequency: 0.01.6 x 10-2) and South Asian in 96 of 10422 chromosomes (frequency: 0.0009). This variant was not identified in the literature nor was it identified in COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), GeneInsight - COGR database, UMD and the NHLBI GO Exome Sequencing Project databases. The c.1039-6dupA variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing; in addition 2 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, this variant meets our laboratory's criteria to be classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004748596	SCV005352441	likely benign	MLH1-related disorder	2024-05-22	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).