Submissions for variant NM_000249.4(MLH1):c.821A>G (p.Lys274Arg)

gnomAD frequency: 0.00001  dbSNP: rs769958855

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481241	SCV000565147	uncertain significance	not provided	2015-02-24	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.821A>G at the cDNA level, p.Lys274Arg (K274R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Lys274Arg 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. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. MLH1 Lys274Arg occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MLH1 Lys274Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000558471	SCV000625200	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-06	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 418300). This missense change has been observed in individual(s) with colorectal cancer, as well as in control individuals from the Icelandic population (PMID: 28466842). This variant is present in population databases (rs769958855, gnomAD 0.0009%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 274 of the MLH1 protein (p.Lys274Arg).
Ambry Genetics	RCV000563768	SCV000669583	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-14	criteria provided, single submitter	clinical testing	The p.K274R variant (also known as c.821A>G), located in coding exon 10 of the MLH1 gene, results from an A to G substitution at nucleotide position 821. The lysine at codon 274 is replaced by arginine, an amino acid with highly similar properties. This alteration has been identified with a carrier frequency of 0.22% in an Icelandic colorectal cancer cohort (Haraldsdottir S et al. Nat Commun, 2017 05;8:14755). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000764482	SCV000895553	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2018-10-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002243	SCV004822006	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing