Submissions for variant NM_000249.4(MLH1):c.96C>G (p.Ile32Met)

dbSNP: rs1553637356

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000544686	SCV000625213	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-04-11	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with personal and/or family history of cancer (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 455465). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with methionine at codon 32 of the MLH1 protein (p.Ile32Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine.
Color Diagnostics, LLC DBA Color Health	RCV000581627	SCV000689935	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 32 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 not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.95T>A (p.Ile32Asn), has been described as disease-causing (ClinVar variation ID: 823364), suggesting that this position is important for the protein function. 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.
GeneKor MSA	RCV000581627	SCV000822027	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000581627	SCV004006418	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-12	criteria provided, single submitter	clinical testing	The p.I32M variant (also known as c.96C>G), located in coding exon 1 of the MLH1 gene, results from a C to G substitution at nucleotide position 96. The isoleucine at codon 32 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition. (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.
All of Us Research Program, National Institutes of Health	RCV004003725	SCV004835237	uncertain significance	Lynch syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 32 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 not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.95T>A (p.Ile32Asn), has been described as disease-causing (ClinVar variation ID: 823364), suggesting that this position is important for the protein function. 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.