Submissions for variant NM_000249.4(MLH1):c.844G>A (p.Ala282Thr)

dbSNP: rs774689817

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534514	SCV000625201	benign	Hereditary nonpolyposis colorectal neoplasms	2024-08-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580834	SCV000684874	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 282 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 been identified in 1/251474 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.
Fulgent Genetics, Fulgent Genetics	RCV000764483	SCV000895554	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580834	SCV004071641	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-30	criteria provided, single submitter	clinical testing	The p.A282T variant (also known as c.844G>A), located in coding exon 10 of the MLH1 gene, results from a G to A substitution at nucleotide position 844. The alanine at codon 282 is replaced by threonine, an amino acid with similar properties. This alteration was reported once in a cohort of patients with breast and/or colorectal cancer in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355010	SCV001549764	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MLH1 p.Ala282Thr variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (ID: rs774689817) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae and Color). The variant was identified in control databases in 1 of 246248 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the Latino population in 1 of 33582 chromosomes (freq: 0.00003), while the variant was not observed in the African, Other, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala282 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.