Submissions for variant NM_000249.4(MLH1):c.842C>G (p.Ala281Gly)

gnomAD frequency: 0.00001  dbSNP: rs63749950

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000792064	SCV000931336	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 281 of the MLH1 protein (p.Ala281Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 639304). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts the p.Ala281 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16995940, 18561205, 26761715; www.insight-database.org). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV001017749	SCV001178881	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-06	criteria provided, single submitter	clinical testing	The p.A281G variant (also known as c.842C>G), located in coding exon 10 of the MLH1 gene, results from a C to G substitution at nucleotide position 842. The alanine at codon 281 is replaced by glycine, an amino acid with 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224470	SCV003920212	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2022-10-05	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF: 0.007% [1/15270]; https://gnomad.broadinstitute.org/variant/3-37017557-C-G?dataset=gnomad_r3). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. A different variant at this same amino acid position (c.842C>T; p.Ala281Val) has been reported as pathogenic (ClinVar Variation ID: 90390); however, studies have shown that the c.842C>T variant causes aberrant splicing and subsequent loss of protein expression, whereas splice prediction tools do not suggest that this variant, c.842C>G, similarly impacts splicing (Lastella 2006 PMID: 16995940; Takahashi 2007 PMID: 17510385). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Color Diagnostics, LLC DBA Color Health	RCV001017749	SCV004359205	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 281 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 not been identified 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.
All of Us Research Program, National Institutes of Health	RCV004001562	SCV004840913	uncertain significance	Lynch syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 281 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 not been identified 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.