Submissions for variant NM_000249.4(MLH1):c.1637A>G (p.Lys546Arg)

gnomAD frequency: 0.00001  dbSNP: rs587779954

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000759809	SCV000149372	uncertain significance	not provided	2021-03-25	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, a Lynch syndrome-associated cancer, and/or polyps (Yurgelun 2015, Nikitin 2020); This variant is associated with the following publications: (PMID: 25980754, 32547938, 32719484)
CSER _CC_NCGL, University of Washington	RCV000211532	SCV000212178	uncertain significance	Lynch syndrome	2015-03-11	criteria provided, single submitter	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000115463	SCV000592412	uncertain significance	not specified	2014-12-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566461	SCV000662039	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-14	criteria provided, single submitter	clinical testing	The p.K546R variant (also known as c.1637A>G), located in coding exon 14 of the MLH1 gene, results from an A to G substitution at nucleotide position 1637. The lysine at codon 546 is replaced by arginine, an amino acid with highly similar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). This variant was identified once in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This variant was identified once in a cohort of 711 hereditary or sporadic breast cancer patients and was not identified in healthy donor controls (n=492) (Nikitin AG et al. Front Oncol, 2020 May;10:666). This alteration was also detected twice in a cohort of 26,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000625759	SCV000746301	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-10	criteria provided, single submitter	clinical testing
Invitae	RCV000629933	SCV000750889	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-10-06	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 546 of the MLH1 protein (p.Lys546Arg). This variant is present in population databases (rs587779954, gnomAD 0.002%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127617). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Counsyl	RCV000662406	SCV000784829	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-12-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759809	SCV000889386	uncertain significance	not provided	2018-05-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000566461	SCV000908638	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 546 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 impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has been identified in 2/251318 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.	RCV000662406	SCV004018150	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-14	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.
Baylor Genetics	RCV000662406	SCV004190617	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-09-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000211532	SCV004843186	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 546 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 impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has been identified in 2/251318 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.