Submissions for variant NM_000249.4(MLH1):c.319A>G (p.Ile107Val)

dbSNP: rs572906317

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000167889	SCV000218535	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	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 107 of the MLH1 protein (p.Ile107Val). This variant is present in population databases (rs572906317, gnomAD 0.003%). 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: 188068). 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%. This variant disrupts the p.Ile107 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8776590, 11555625, 11793442, 12810663, 16083711, 17510385, 21120944). 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.
GeneDx	RCV000586116	SCV000569868	uncertain significance	not provided	2022-10-28	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22753075, 16083711, 21120944)
Color Diagnostics, LLC DBA Color Health	RCV000583427	SCV000689879	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 107 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 1/251416 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense mutations at the same codon, p.Ile107Arg and p.Ile107Lys, are considered to be disease-causing (ClinVar variation ID: 659950, 90167), suggesting 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586116	SCV000696161	uncertain significance	not provided	2016-04-01	criteria provided, single submitter	clinical testing	Variant summary: The c.319A>G variant affects a conserved nucleotide resulting in amino acid change from Ile to Val. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant is found in 1/121398 control chromosomes at a frequency of 0.0000082, which does not exceed the maximal expected frequency of a pathogenic allele (0.0007105). In addition, one clinical laboratory classified this variant as VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor was it evaluated for functional impact by in vivo/vitro studies. Due to the absence of clinical information and lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Ambry Genetics	RCV000583427	SCV001180449	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-13	criteria provided, single submitter	clinical testing	The p.I107V variant (also known as c.319A>G), located in coding exon 4 of the MLH1 gene, results from an A to G substitution at nucleotide position 319. The isoleucine at codon 107 is replaced by valine, an amino acid with highly similar properties. This variant was identified in a cohort of 882 Chinese individuals with a personal and/or family history of breast or ovarian cancers who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci, 2020 Feb;111:647-657). 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.
All of Us Research Program, National Institutes of Health	RCV001357822	SCV004835266	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 107 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 hereditary cancer in the literature. This variant has been identified in 1/251416 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357822	SCV001553409	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MLH1 p.Ile107Val variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs572906317) as “With Uncertain significance allele”, and in ClinVar (as uncertain significance by Invitae, GeneDx, Color Genomics, and Laboratory Corporation of America). The variant was identified in control databases in 1 of 246182 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was observed in the Latino population in 1 of 33580 chromosomes (freq: 0.00003), but not in the African, Other, European (Non-Finnish), Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. Although the p.Ile107Val does not appear in the literature, a different amino acid substitution at the same site, p.Ile107Arg has been reported in individuals affected with Lynch syndrome, and a functional study has been demonstrated to produce a nonfunctional protein, and can be considered disease causing, suggesting that the isoleucine 107 residue is critical for MLH1 protein function (Nyström_Lahti_2002). The p.Ile107Val residue is conserved in mammals however, the variant amino acid Valine (Val) is present in the African clawed frog, increasing the likelihood that this variant does not have clinical significance. In addition, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of the consensus splice site; however, 4 out of 5 programs predict an altered 5' splice site 13bp into the exon away from the splice acceptor site and we cannot eliminate the possibility that this may lead to abnormal splicing or creation of a cryptic splice site. 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.