Submissions for variant NM_000249.4(MLH1):c.144A>C (p.Gln48His)

gnomAD frequency: 0.00001  dbSNP: rs147342421

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520645	SCV000616779	uncertain significance	not provided	2023-07-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual undergoing multi-gene cancer panel testing due to a personal history of a Lynch syndrome-related cancer and/or polyps (Yurgelun et al., 2015); This variant is associated with the following publications: (PMID: 22753075, 25980754)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543077	SCV000625068	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 48 of the MLH1 protein (p.Gln48His). This variant is present in population databases (rs147342421, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 449060). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt MLH1 function with a negative predictive value of 95%. This variant disrupts the p.Gln48 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19386570, 21404117, 22395473, 24362816). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV000579927	SCV000684744	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000663271	SCV000786503	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2018-05-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000579927	SCV001171984	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	The p.Q48H variant (also known as c.144A>C), located in coding exon 2 of the MLH1 gene, results from an A to C substitution at nucleotide position 144. The glutamine at codon 48 is replaced by histidine, an amino acid with highly similar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc.	RCV000663271	SCV004020266	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-10	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000663271	SCV005057946	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2024-03-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000520645	SCV005623553	uncertain significance	not provided	2024-11-15	criteria provided, single submitter	clinical testing	The MLH1 c.144A>C (p.Gln48His) variant has been reported in the published literature in individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (PMID: 25980754 (2015)). In a large scale breast cancer association study, this variant has been observed in a breast cancer case (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.0002 (5/24970 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.