Submissions for variant NM_000249.4(MLH1):c.1896+7C>T

gnomAD frequency: 0.00001  dbSNP: rs863224339

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000198196	SCV000253136	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000411286	SCV000489668	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2016-11-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000419669	SCV000533051	likely benign	not specified	2016-10-19	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.
Color Diagnostics, LLC DBA Color Health	RCV000579905	SCV000684781	likely benign	Hereditary cancer-predisposing syndrome	2016-09-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000411286	SCV001136428	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000419669	SCV001362940	uncertain significance	not specified	2019-03-08	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1896+7C>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. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246158 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1896+7C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four 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 likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000411286	SCV004018098	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-13	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477654	SCV004220857	uncertain significance	not provided	2023-05-14	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000017 (2/114450 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect MLH1 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV003895263	SCV004715453	likely benign	MLH1-related condition	2023-02-15	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).