Submissions for variant NM_000249.4(MLH1):c.682C>A (p.Leu228Met)

gnomAD frequency: 0.00001  dbSNP: rs751628735

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163166	SCV000213684	likely benign	Hereditary cancer-predisposing syndrome	2023-02-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Counsyl	RCV000409697	SCV000487823	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2015-11-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000587335	SCV000618186	uncertain significance	not provided	2023-06-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual undergoing genetic testing with a personal or family history of hereditary breast and ovarian cancer syndrome related cancers (Lesueur et al., 2021); This variant is associated with the following publications: (PMID: 23338612, 33471991, 22753075, 34359559)
Invitae	RCV000558825	SCV000625186	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 228 of the MLH1 protein (p.Leu228Met). This variant is present in population databases (rs751628735, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 184050). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000163166	SCV000684859	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 228 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control study, this variant has been reported in 9/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 7/282172 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587335	SCV000696176	uncertain significance	not provided	2016-08-01	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.682C>A affects a non-conserved nucleotide and results in a replacement of a Leucine (L) with a Methionine (M). Both residues are medium size and hydrophobic, therefore this Leucine to Methionine substitution does not alter the physico-chemical properties of the protein. 3/4 in silico tools predict the variant to be disease causing. It was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0026% which does not exceed the maximal allele frequency of a disease causing MLH1 allele (0.07%) to exclude pathogenicity. To our knowledge, the variant has not been reported in affected patients from the literature and in vitro/vivo studies to assess the functional impact of the variant have not been published either. Clinical diagnostic centers classify variant as Uncertain via ClinVar (without evidence to independently evaluate). Due to the lack of clinical and functional data, the variant was classified as a variant of uncertain significance until more information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587335	SCV000889403	uncertain significance	not provided	2022-08-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163166	SCV002528772	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000409697	SCV004018099	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-13	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: 25085752].
Baylor Genetics	RCV000409697	SCV004195080	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995237	SCV004840894	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 228 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 7/282172 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202192	SCV000257114	uncertain significance	not specified		no assertion criteria provided	research