Submissions for variant NM_007294.4(BRCA1):c.4083G>A (p.Met1361Ile)

dbSNP: rs374192364

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129891	SCV000184708	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	The p.M1361I variant (also known as c.4083G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4083. The methionine at codon 1361 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000766669	SCV000570599	uncertain significance	not provided	2016-06-08	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.4083G>A at the cDNA level, p.Met1361Ile (M1361I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). Using alternate nomenclature, this variant would be defined as BRCA1 4202G>A. This variant has been observed in at least one individual with ovarian cancer (Alsop 2012). BRCA1 Met1361Ile was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Met1361Ile occurs at a position that is not conserved and is located within the SCD domain and a region known to interact with multiple proteins (Narod 2004, Clark 2012, Paul 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Met1361Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000637459	SCV000758919	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-07-12	criteria provided, single submitter	clinical testing	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 BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 37564). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is present in population databases (rs374192364, gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1361 of the BRCA1 protein (p.Met1361Ile). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Genetic Services Laboratory, University of Chicago	RCV001818194	SCV002067115	uncertain significance	not specified	2018-05-23	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129891	SCV003847554	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Color Diagnostics, LLC DBA Color Health	RCV000129891	SCV004360196	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 1361 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 1/250760 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.
Sharing Clinical Reports Project (SCRP)	RCV000031145	SCV000053745	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2011-03-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000478992	SCV000591485	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Met1361Ile variant has not been previously reported in the literature nor by our laboratory. The p.Met1361 residue is not conserved in mammals and other species and in-silico or computational analyses (PolyPhen, SIFT and AlignGVGD) do not suggest a high likelihood of impact to the protein, but this information is not predictive enough to rule out pathogenicity. In summary, based on the current information presented above, this variant is classified as Variant of Unknown Significance (VUS).