Submissions for variant NM_000249.4(MLH1):c.1327A>C (p.Lys443Gln)

gnomAD frequency: 0.00001  dbSNP: rs34213726

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219360	SCV000274375	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-19	criteria provided, single submitter	clinical testing	The p.K443Q variant (also known as c.1327A>C), located in coding exon 12 of the MLH1 gene, results from an A to C substitution at nucleotide position 1327. The lysine at codon 443 is replaced by glutamine, an amino acid with similar properties. This alteration was detected in a patient with a MSI-High colorectal cancer (CRC) that showed loss of MLH1 and PMS2 on IHC, and another patient with CRC that showed loss of MLH1 on IHC (Hampel, H et al. N Engl J Med. 2005 May 5;352(18):1851-60; Drost M, Hum. Mutat. 2010 Mar; 31(3):247-53). However, multiple studies have shown normal MLH1 functional activity (Raevaara TE, Gastroenterology 2005 Aug; 129(2):537-49; Andersen SD, Hum. Mutat. 2012 Dec; 33(12):1647-55; Drost M, Hum. Mutat. 2010 Mar; 31(3):247-53). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001703974	SCV000292610	likely benign	not provided	2019-04-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24933000, 17594722, 22753075, 21120944, 16083711, 21136174, 22949387, 17192056, 20020535, 22045683, 15872200)
Invitae	RCV000697163	SCV000825760	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 443 of the MLH1 protein (p.Lys443Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer and gastric cancer (PMID: 15099349, 15872200, 16083711). ClinVar contains an entry for this variant (Variation ID: 89698). 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%. Experimental studies have shown that this missense change does not substantially affect MLH1 function (PMID: 16083711, 20020535, 21136174, 22753075). 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	RCV000219360	SCV000906441	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-02	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamine at codon 443 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies using recombinant human cells or cell-free assays reported that this variant has mismatch repair activity, localization, and expression comparable to wild type (PMID: 16083711, 20020535). This variant has been reported in individuals affected with Lynch syndrome (PMID: 15872200, 16083711, 22753075) and in an individual affected with gastric cancer (PMID: 15099349). This variant has been identified in 1/31370 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.
All of Us Research Program, National Institutes of Health	RCV003997108	SCV004840991	uncertain significance	Lynch syndrome	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamine at codon 443 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies using recombinant human cells or cell-free assays reported that this variant has mismatch repair activity, localization, and expression comparable to wild type (PMID: 16083711, 20020535). This variant has been reported in individuals affected with Lynch syndrome (PMID: 15872200, 16083711, 22753075) and in an individual affected with gastric cancer (PMID: 15099349). This variant has been identified in 1/31370 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.
Pathway Genomics	RCV000144608	SCV000189935	uncertain significance	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing