Submissions for variant NM_000249.4(MLH1):c.116+8G>A

gnomAD frequency: 0.00001  dbSNP: rs904872305

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000431627	SCV000530359	likely benign	not specified	2016-07-26	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.
Invitae	RCV000471339	SCV000555958	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000431627	SCV000919649	uncertain significance	not specified	2018-06-04	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.116+8G>A alters a 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 244694 control chromosomes (gnomAD and publication). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.116+8G>A, has been reported in the literature in a family that did not fulfill Amsterdam criteria (Pastrello_2011). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001188614	SCV001355698	likely benign	Hereditary cancer-predisposing syndrome	2019-07-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000431627	SCV002070094	uncertain significance	not specified	2020-01-16	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MLH1 gene demonstrated a sequence change in intron 1, c.116+8G>A. This sequence change does not appear to have been previously described in patients with MLH1-related disorders and has been described in the gnomAD database in one individual (rs904872305). This sequence change is not clearly predicted to have a deleterious effect on splicing based on in silico splice prediction programs. It is possible that this sequence change represents a benign sequence change in the MLH1 gene that has not been identified to date. The functional significance of this sequence change is not known at present and its contribution to this patient's disease phenotype cannot definitively be determined.