Submissions for variant NM_000249.4(MLH1):c.1359G>C (p.Lys453Asn)

gnomAD frequency: 0.00001  dbSNP: rs756099600

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167968	SCV000218616	benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000214998	SCV000273733	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-22	criteria provided, single submitter	clinical testing	The p.K453N variant (also known as c.1359G>C), located in coding exon 12 of the MLH1 gene, results from a G to C substitution at nucleotide position 1359. The lysine at codon 453 is replaced by asparagine, an amino acid with similar properties. In one study, this variant was reported in 1/1893 women with epithelial ovarian cancer (Pal T et al. Br. J. Cancer. 2012 Nov; 107(10):1783-90). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590046	SCV000696106	uncertain significance	not provided	2016-09-09	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.1359G>C (p.Lys453Asn) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 1/121006 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). This variant has been reported in one OvC patient without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until more evidence becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000214998	SCV000910896	likely benign	Hereditary cancer-predisposing syndrome	2015-11-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000590046	SCV002097443	uncertain significance	not provided	2023-12-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33471991, 22753075, 29684080, 34326862, 23047549)
Sema4, Sema4	RCV000214998	SCV002528642	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-08	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003995601	SCV004840995	likely benign	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004567360	SCV005057960	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2024-03-13	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004567360	SCV005897183	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2024-11-22	criteria provided, single submitter	clinical testing	This variant is considered likely 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: 27363726].