Submissions for variant NM_000249.4(MLH1):c.885-5G>T

gnomAD frequency: 0.00001  dbSNP: rs267607802

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075917	SCV000106936	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Intronic substitution with no effect on splicing, tested with NMD inhibitor
GeneDx	RCV000585990	SCV000211137	likely benign	not provided	2021-02-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 12624141, 18561205, 22949379)
Ambry Genetics	RCV000160558	SCV000216095	likely benign	Hereditary cancer-predisposing syndrome	2018-06-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV001080675	SCV000253145	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160558	SCV000684879	likely benign	Hereditary cancer-predisposing syndrome	2022-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000417381	SCV000696187	likely benign	not specified	2023-02-06	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.885-5G>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. Consistently, functional analysis using the pCAS ex vivo splicing assay and RNA analysis demonstrated this variant had no effect (Tournier_2008).The variant allele was found at a frequency of 2e-05 in 251406 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.885-5G>T has been reported in the literature in at-least one proband referred to a French family cancer clinic and satisfying at least one of the modified Amsterdam criteria (Parc_2003). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000585990	SCV000889408	likely benign	not provided	2022-09-26	criteria provided, single submitter	clinical testing
Mendelics	RCV000987159	SCV001136390	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160558	SCV002528786	likely benign	Hereditary cancer-predisposing syndrome	2020-12-18	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492418	SCV004239267	likely benign	Breast and/or ovarian cancer	2023-06-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003894922	SCV004713564	likely benign	MLH1-related condition	2023-01-11	criteria provided, single submitter	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000585990	SCV001549002	likely benign	not provided		no assertion criteria provided	clinical testing	The MLH1 c.885-5G>T variant was identified in 1 of 872 proband chromosomes (frequency: 0.001) from French individuals or families with HNPCC (Parc 2003). The variant was also identified in dbSNP (ID: rs267607802) as “With other allele”, ClinVar (classified as likely benign by an InSiGHT expert panel (2013), GeneDx, Invitae, Ambry Genetics, and 3 other submitters; and as benign by Color), and UMD-LSDB (classified neutral). The variant was identified in control databases in 5 of 246182 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: Latino in 1 of 33582 chromosomes (freq: 0.00003) and European Non-Finnish in 4 of 111640 chromosomes (freq: 0.00004), while it was not observed in the African, Other, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The c.885-5G>T 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 and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. However, one study using both a minigene assay and RT-PCR on patient RNA showed that this variant has no effect on splicing (Tournier 2008). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.