Submissions for variant NM_000249.4(MLH1):c.743A>G (p.Asn248Ser)

gnomAD frequency: 0.00001  dbSNP: rs587782800

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132357	SCV000187446	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	The p.N248S variant (also known as c.743A>G), located in coding exon 9 of the MLH1 gene, results from an A to G substitution at nucleotide position 743. The asparagine at codon 248 is replaced by serine, an amino acid with highly similar properties. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471668	SCV000543549	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 248 of the MLH1 protein (p.Asn248Ser). This variant is present in population databases (rs587782800, gnomAD 0.007%). This missense change has been observed in individual(s) with MLH1-related conditions (PMID: 35171259, 35449176). ClinVar contains an entry for this variant (Variation ID: 142890). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt MLH1 function with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780419	SCV000917657	uncertain significance	not specified	2018-07-19	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.743A>G (p.Asn248Ser) results in a conservative amino acid change located in the N-terminal DNA mismatch repair protein family domain (IPR002099) and DNA mismatch repair protein, S5 domain 2-like (IPR013507) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 246106 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.743A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000987157	SCV001136384	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132357	SCV001347235	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 248 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 4/251252 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.
Baylor Genetics	RCV000987157	SCV004195065	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001528459	SCV005623590	uncertain significance	not provided	2024-10-16	criteria provided, single submitter	clinical testing	The MLH1 c.743A>G (p.Asn248Ser) variant has been reported in the published literature in individuals with breast cancer (PMID: 35449176 (2022)) and pancreatic cancer (PMID: 35171259 (2022)). The frequency of this variant in the general population, 0.000016 (4/251252 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005359303	SCV005916910	uncertain significance	Muir-Torré syndrome	2021-03-12	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528459	SCV001740247	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001528459	SCV001956364	uncertain significance	not provided		no assertion criteria provided	clinical testing