Submissions for variant NM_000249.4(MLH1):c.91G>A (p.Ala31Thr)

dbSNP: rs749671520

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487360	SCV000569949	uncertain significance	not provided	2023-09-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22753075, 16083711, 21120944)
Ambry Genetics	RCV000569326	SCV000676040	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-04	criteria provided, single submitter	clinical testing	The p.A31T variant (also known as c.91G>A), located in coding exon 1 of the MLH1 gene, results from a G to A substitution at nucleotide position 91. The alanine at codon 31 is replaced by threonine, an amino acid with similar properties. 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.
Fulgent Genetics, Fulgent Genetics	RCV000765728	SCV000897096	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816684	SCV000957202	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 31 of the MLH1 protein (p.Ala31Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 34284872). ClinVar contains an entry for this variant (Variation ID: 420921). 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 expected to disrupt MLH1 protein function with a positive 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.
Color Diagnostics, LLC DBA Color Health	RCV000569326	SCV001354731	uncertain significance	Hereditary cancer-predisposing syndrome	2019-01-04	criteria provided, single submitter	clinical testing
Department of Human Genetics, Hannover Medical School	RCV004704020	SCV005255781	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2024-09-16	criteria provided, single submitter	clinical testing