Submissions for variant NM_000249.4(MLH1):c.482C>T (p.Thr161Met)

gnomAD frequency: 0.00002  dbSNP: rs763992299

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483884	SCV000570850	uncertain significance	not provided	2022-08-29	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: 29887214, 34416543, 22753075, 25980754)
Ambry Genetics	RCV000574536	SCV000673818	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-11	criteria provided, single submitter	clinical testing	The p.T161M variant (also known as c.482C>T), located in coding exon 6 of the MLH1 gene, results from a C to T substitution at nucleotide position 482. The threonine at codon 161 is replaced by methionine, an amino acid with 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). In addition, using a Bayesian analysis that incorporates tumor mutation data, this alteration was classified as a variant of unknown significance (Shirts BH et al. Am J Hum Genet, 2018 07;103:19-29). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758571	SCV000887311	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MLH1 NM_000249.3:c.482C>T has a 14.6% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001054721	SCV001219070	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-04-15	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 161 of the MLH1 protein (p.Thr161Met). This variant is present in population databases (rs763992299, gnomAD 0.004%). This missense change has been observed in individual(s) with a history of Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 421591). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. 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.