Submissions for variant NM_000249.4(MLH1):c.1564C>T (p.Arg522Trp)

gnomAD frequency: 0.00002  dbSNP: rs63751703

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000195882	SCV000254354	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 522 of the MLH1 protein (p.Arg522Trp). This variant is present in population databases (rs63751703, gnomAD 0.004%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 27601186). ClinVar contains an entry for this variant (Variation ID: 216331). 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: 23403630). 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.
Ambry Genetics	RCV000216499	SCV000273158	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-17	criteria provided, single submitter	clinical testing	The p.R522W variant (also known as c.1564C>T), located in coding exon 14 of the MLH1 gene, results from a C to T substitution at nucleotide position 1564. The arginine at codon 522 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was reported in a Swedish family suspected to have Lynch syndrome, but no clinical or family history information was provided (Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36(5):2823-2835). In another study, the p.R522W alteration was detected as a somatic alteration in a Dukes' B2 colon cancer that exhibited microsatellite stability (Kámory E et al. Pathol. Oncol. Res. 2003;9(4): 236-41). Functional analyses of this alteration using quantitative PCR, pulse-chase and thermal stability indicate that p.R522W does not have a significant decrease in expression or MMR proficiency compared to wild-type (Hinrichsen I et al. Clin. Cancer Res. 2013 May;19(9):2432-41). This amino acid position is not well 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.
Counsyl	RCV000412186	SCV000488515	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-04-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000587282	SCV000569952	uncertain significance	not provided	2023-06-13	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 with personal/family history suspicious for Lynch syndrome (Lagerstedt-Robinson et al., 2016); Published functional studies are inconclusive: slightly reduced protein expression but mismatch repair activity comparable to wild-type (Hinrichsen et al., 2013); This variant is associated with the following publications: (PMID: 26976419, 14688830, 24362816, 22753075, 12799449, 20533529, 23403630, 27601186)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587282	SCV000696116	uncertain significance	not provided	2016-06-06	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.1564C>T (p.Arg522Trp) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 4/121218 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). In addition, multiple clinical diagnostic laboratories classified this variant as VUS, without evidence to independently evaluate. This variant, to our knowledge, has not been reported as a germ-line variant in affected individuals. One study showed this variant with protein expression level not significantly different from WT (Hinrichsen_2013). Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
PreventionGenetics, part of Exact Sciences	RCV000587282	SCV000805952	uncertain significance	not provided	2017-12-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216499	SCV000911976	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 522 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). An experimental functional study has shown this variant had normal mismatch repair activity and only a moderate impact on MLH1 expression (PMID: 23403630). This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 27601186). This variant has been identified in 5/282468 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.
Myriad Genetics, Inc.	RCV000412186	SCV004018111	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-13	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.
All of Us Research Program, National Institutes of Health	RCV003997006	SCV004841041	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 522 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. An experimental functional study has shown this variant had normal mismatch repair activity and only a moderate impact on MLH1 expression (PMID: 23403630). This variant has been reported in an individual suspected of having Lynch syndrome in the literature (PMID: 27601186). This variant has been identified in 5/282468 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.