Submissions for variant NM_000249.4(MLH1):c.1172A>G (p.Gln391Arg)

dbSNP: rs587782884

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132521	SCV000187618	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-05	criteria provided, single submitter	clinical testing	The p.Q391R variant (also known as c.1172A>G), located in coding exon 12 of the MLH1 gene, results from an A to G substitution at nucleotide position 1172. The glutamine at codon 391 is replaced by arginine, an amino acid with highly similar properties. This alteration was observed in a patient with ovarian cancer diagnosed at age 53 who did not have a family history of cancer; it was classified as a variant of unknown significance (Kraus C et al. Int. J. Cancer 2017 Jan;140(1):95-102). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759079	SCV000888173	uncertain significance	not provided	2020-10-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132521	SCV000904058	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 391 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: 27616075). This variant has been identified in 1/251400 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202075	SCV000917664	uncertain significance	not specified	2018-11-29	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1172A>G (p.Gln391Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246166 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1172A>G has been reported in the literature in an individual affected with ovarian cancer (Kraus_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV000811189	SCV000951443	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 391 of the MLH1 protein (p.Gln391Arg). This variant is present in population databases (rs587782884, gnomAD 0.0009%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 27616075). ClinVar contains an entry for this variant (Variation ID: 143002). 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%. 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	RCV000759079	SCV001873642	uncertain significance	not provided	2021-08-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with ovarian cancer (Kraus 2017); This variant is associated with the following publications: (PMID: 27616075)
All of Us Research Program, National Institutes of Health	RCV003998150	SCV004840968	uncertain significance	Lynch syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 391 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: 27616075). This variant has been identified in 1/251400 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202075	SCV000257047	uncertain significance	not specified		no assertion criteria provided	research