Submissions for variant NM_005591.4(MRE11):c.529G>A (p.Ala177Thr)

gnomAD frequency: 0.00010  dbSNP: rs142996063

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656867	SCV000149828	uncertain significance	not provided	2021-01-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including breast, ovarian, and colorectal cancer (Castera 2014, Belhadj 2020); This variant is associated with the following publications: (PMID: 32449991, 24549055, 31159747)
Ambry Genetics	RCV000115919	SCV000183953	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-15	criteria provided, single submitter	clinical testing	The p.A177T variant (also known as c.529G>A), located in coding exon 5 of the MRE11A gene, results from a G to A substitution at nucleotide position 529. The alanine at codon 177 is replaced by threonine, an amino acid with similar properties. This variant has been reported in studies of patients with triple negative breast cancer who were unselected for family history of breast or ovarian cancer, in BRCA1/2-negative patients with early-onset breast cancer, and in patients with familial breast cancer and other hereditary cancers (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8; Li J et al. J. Med. Genet. 2016 Jan;53:34-42; Tsaousis GN et al. BMC Cancer 2019 Jun;19(1):535). This variant was also identified in 1 of 523 BRCA1/2 negative male breast cancer patients undergoing multigene panel testing (Rizzolo P et al. Int J Cancer, 2019 Jul;145:390-400). 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	RCV000791435	SCV000254867	uncertain significance	Ataxia-telangiectasia-like disorder	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 177 of the MRE11 protein (p.Ala177Thr). This variant is present in population databases (rs142996063, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with a personal and/or family history of breast or ovarian cancer (PMID: 24549055, 25452441, 26534844). ClinVar contains an entry for this variant (Variation ID: 127983). 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.
Illumina Laboratory Services, Illumina	RCV000400887	SCV000374941	uncertain significance	Ataxia-telangiectasia-like disorder 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Athena Diagnostics Inc	RCV000212559	SCV000614126	likely benign	not specified	2020-09-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000400887	SCV000785465	uncertain significance	Ataxia-telangiectasia-like disorder 1	2017-08-15	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000115919	SCV000822037	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000400887	SCV000894682	uncertain significance	Ataxia-telangiectasia-like disorder 1	2018-10-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115919	SCV002538430	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-17	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656867	SCV004220925	likely benign	not provided	2023-02-28	criteria provided, single submitter	clinical testing