Submissions for variant NM_000249.4(MLH1):c.2173C>G (p.Arg725Gly)

dbSNP: rs138584384

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217046	SCV000273152	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-12	criteria provided, single submitter	clinical testing	The p.R725G variant (also known as c.2173C>G), located in coding exon 19 of the MLH1 gene, results from a C to G substitution at nucleotide position 2173. The arginine at codon 725 is replaced by glycine, an amino acid with dissimilar properties. This alteration was previously reported in at least one individual from a cohort of 278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet. Med. 2015 Aug;17(8):630-8). 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.
Invitae	RCV000461789	SCV000543651	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-02-01	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. ClinVar contains an entry for this variant (Variation ID: 229812). This missense change has been observed in individual(s) with breast cancer and/or colorectal cancer (PMID: 25503501, 34347074). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 725 of the MLH1 protein (p.Arg725Gly).
Counsyl	RCV000663259	SCV000786487	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2018-05-11	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000663259	SCV004020263	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-10	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.
All of Us Research Program, National Institutes of Health	RCV003997772	SCV004843292	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 725 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 been reported in at least one individual with early onset breast cancer (PMID: 25503501) as well as an individual affected with colorectal cancer (PMID: 34347074). This variant has been identified in 2/251148 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.