Submissions for variant NM_000249.4(MLH1):c.94A>G (p.Ile32Val)

gnomAD frequency: 0.00003  dbSNP: rs2020872

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524324	SCV000259953	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-11	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 32 of the MLH1 protein (p.Ile32Val). This variant is present in population databases (rs2020872, gnomAD 0.01%). 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: 36560). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 12810663, 18373977). 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.
GeneDx	RCV000217828	SCV000279736	uncertain significance	not provided	2023-09-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with breast cancer (Guindalini et al., 2022; Hu et al., 2022); Published functional studies demonstrate interaction with PMS2 and EXO1 as well as beta-galactosidase activity similar to wildtype, and reduced interaction with MRE11 (Zhao et al., 2008; Kondo et al., 2003); This variant is associated with the following publications: (PMID: 22290698, 22949387, 18373977, 22753075, 16083711, 21120944, 27527004, 18383312, 35264596, 15184898, 35449176, 12810663, 32566746, 26934580, 36243179)
Ambry Genetics	RCV000568967	SCV000662074	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	The p.I32V variant (also known as c.94A>G), located in coding exon 1 of the MLH1 gene, results from an A to G substitution at nucleotide position 94. The isoleucine at codon 32 is replaced by valine, an amino acid with highly similar properties. An in vitro two-hybrid yeast functional assay showed that this variant maintained MLH1 interactions with PMS2 and EXO1, with little to no reduction from wild type activity (Kondo E et al. Cancer Res. 2003 Jun;63:3302-8). This alteration has been detected in a cohort of Israeli familial colorectal cancer probands (Lipkin SM et al. Nat Genet, 2004 Jul;36:694-9). This amino acid position is 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.
Mendelics	RCV000030233	SCV000837992	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000568967	SCV000903216	likely benign	Hereditary cancer-predisposing syndrome	2015-12-14	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030560	SCV001193604	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000217828	SCV004220906	uncertain significance	not provided	2023-08-23	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in affected individuals with breast cancer (PMIDs: 35264596 (2022) and 35449176 (2022)), biliary tract cancer (PMID: 36243179 (2022)), and colorectal cancer (PMID: 15184898 (2004)). Yeast based functional assays demonstrated little to no protein impact, variant performed similar to wild type (PMIDs: 12810663 (2003) and 18373977 (2008)). The frequency of this variant in the general population, 0.000011 (3/282494 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000030233	SCV004835235	likely benign	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030233	SCV000052900	uncertain significance	Lynch syndrome	2015-10-02	no assertion criteria provided	clinical testing