Submissions for variant NM_000249.4(MLH1):c.415C>G (p.Pro139Ala)

dbSNP: rs779562531

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166916	SCV000217735	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-24	criteria provided, single submitter	clinical testing	The p.P139A variant (also known as c.415C>G), located in coding exon 5 of the MLH1 gene, results from a C to G substitution at nucleotide position 415. The proline at codon 139 is replaced by alanine, an amino acid with highly similar properties. This alteration was detected in one individual with ovarian cancer from a cohort of 1462 patients who underwent multigene panel testing (Shirts BH et al. Genet. Med., 2016 Oct;18:974-81). 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.
Invitae	RCV000524299	SCV000259548	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 139 of the MLH1 protein (p.Pro139Ala). This variant is present in population databases (rs779562531, gnomAD 0.0009%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 187211). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000204264	SCV000266181	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000521531	SCV000617972	uncertain significance	not provided	2017-04-20	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.415C>G at the cDNA level, p.Pro139Ala (P139A) at the protein level, and results in the change of a Proline to an Alanine (CCT>GCT). This variant has been reported in at least one individual with ovarian cancer (Shirts 2016). MLH1 Pro139Ala was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Alanine differ in some properties, this is considered a semi-conservative amino acid substitution. MLH1 Pro139Ala occurs at a position that is conserved across species and is located in the N-terminal ATPase domain (Andersen 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Pro139Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl	RCV000662504	SCV000785028	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-03-16	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662504	SCV004018115	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-13	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000662504	SCV004193001	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-05-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166916	SCV004359183	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 139 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 been reported in an individual affected with ovarian cancer (PMID: 26845104). This variant has been identified in 1/251438 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.