Submissions for variant NM_000249.4(MLH1):c.170A>C (p.Lys57Thr)

dbSNP: rs587779955

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212514	SCV000149373	uncertain significance	not provided	2013-12-10	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.170A>C at the cDNA level, p.Lys57Thr (K57T) at the protein level, and results in the change of a Lysine to a Threonine (AAG>ACG). This variant has not, to our knowledge, been reported as a pathogenic variant or a benign polymorphism. MLH1 Lys57Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a semi-conservative substitution of a positive polar amino acid for a neutral polar one, altering a position that is well conserved throughout evolution and is located in the GHKL (Gyrase, Hsp90, Histidine Kinase, MutL) functional domain, an ATPase domain (Punta 2012). Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. Based on currently available information, it is unclear whether MLH1 Lys57Thr is a pathogenic variant or a rare benign variant.
Ambry Genetics	RCV000115464	SCV000186176	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-09	criteria provided, single submitter	clinical testing	The p.K57T variant (also known as c.170A>C), located in coding exon 2 of the MLH1 gene, results from an A to C substitution at nucleotide position 170. The lysine at codon 57 is replaced by threonine, an amino acid with similar properties. This variant was observed in an individual with breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). 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.
Invitae	RCV000816365	SCV000956869	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 57 of the MLH1 protein (p.Lys57Thr). This variant is not present in population databases (gnomAD no frequency). 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: 127618). 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.
Color Diagnostics, LLC DBA Color Health	RCV000115464	SCV004359165	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-29	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 57 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627). This variant has not been identified 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.
All of Us Research Program, National Institutes of Health	RCV003997262	SCV004835243	uncertain significance	Lynch syndrome	2023-08-14	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 57 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627). This variant has not been identified 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.