Submissions for variant NM_000249.4(MLH1):c.728A>G (p.Asn243Ser)

dbSNP: rs1199917094

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000777146	SCV000912835	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 243 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). 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 1/251284 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.
Invitae	RCV001869118	SCV002155840	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-09-01	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 631100). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 243 of the MLH1 protein (p.Asn243Ser).
Ambry Genetics	RCV000777146	SCV002669210	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-28	criteria provided, single submitter	clinical testing	The p.N243S variant (also known as c.728A>G), located in coding exon 9 of the MLH1 gene, results from an A to G substitution at nucleotide position 728. The asparagine at codon 243 is replaced by serine, an amino acid with highly similar properties. This amino acid position is not well 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.
All of Us Research Program, National Institutes of Health	RCV004001490	SCV004840901	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000777146	SCV005045434	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-05	criteria provided, single submitter	clinical testing