Submissions for variant NM_000249.4(MLH1):c.376T>A (p.Tyr126Asn)

gnomAD frequency: 0.00003  dbSNP: rs200076893

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524295	SCV000254369	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 126 of the MLH1 protein (p.Tyr126Asn). This variant is present in population databases (rs200076893, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18561205, 24383517, 30998989). ClinVar contains an entry for this variant (Variation ID: 90184). An algorithm developed specifically for the MLH1 gene suggests that this missense change is likely to be deleterious (PMID: 22290698). Experimental studies have shown that this missense change does not substantially affect MLH1 function (PMID: 30998989). 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.
GeneDx	RCV000217922	SCV000279071	uncertain significance	not provided	2022-12-01	criteria provided, single submitter	clinical testing	Observed in individuals with colorectal cancer, breast cancer, and/or polyps (Stigliano et al., 2014; Bouvet et al., 2019); Published functional studies demonstrate no damaging effect: variant classified as not pathogenic based on cell survival assay (Bouvet et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24383517, 27527004, 22290698, 18561205, 26333163, 26659599, 22788692, 22753075, 30998989, 16451135)
Counsyl	RCV000410157	SCV000489372	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-09-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571582	SCV000662020	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	The p.Y126N variant (also known as c.376T>A), located in coding exon 4 of the MLH1 gene, results from a T to A substitution at nucleotide position 376. The tyrosine at codon 126 is replaced by asparagine, an amino acid with dissimilar properties. This alteration has been reported as an uncertain variant in a patient diagnosed with colon cancer at age <50 whose family met Amsterdam II criteria. The patient's tumor was MSI-H and lacked MLH1 on IHC (Stigliano V et al. J Exp Clin Cancer Res. 2014 Jan; 33:1). This alteration was reported in another patient with a personal history of endometrial cancer undergoing genetic testing due to a clinical suspicion of Lynch syndrome. The patient's tumor was MSI-H and lacked MLH1 and PMS2 on IHC (Liccardo R et al. Int J Mol Med, 2022 Jun;49:). This amino acid position is 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.
Color Diagnostics, LLC DBA Color Health	RCV000571582	SCV000684824	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-15	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with asparagine at codon 126 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). A functional study has shown that this variant does not affect MLH1 protein function in a methylation tolerance-based assay (PMID: 30998989). This variant has been observed in an individual affected with colorectal cancer and a Lynch syndrome family (PMID: 18561205, 24383517). This variant has been identified in 11/282808 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000217922	SCV001134311	uncertain significance	not provided	2019-07-02	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149739	SCV003838203	uncertain significance	Breast and/or ovarian cancer	2022-06-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410157	SCV004018186	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-15	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000410157	SCV004195099	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-09-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997129	SCV004835278	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with asparagine at codon 126 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). A functional study has shown that this variant does not affect MLH1 protein function in a methylation tolerance-based assay (PMID: 30998989). This variant has been observed in an individual affected with colorectal cancer and a Lynch syndrome family (PMID: 18561205, 24383517). This variant has been identified in 11/282808 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.