Submissions for variant NM_007294.4(BRCA1):c.3042G>A (p.Met1014Ile)

dbSNP: rs1555588493

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587781	SCV000698999	uncertain significance	not provided	2016-08-03	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.3042G>A (p.Met1014Ile) variant involves the alteration of a non-conserved nucleotide and results in a replacement of a medium size and hydrophobic Methionine (M) with a medium size and hydrophobic Isoleucine (I). 4/4 in silico tools predict a benign outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant is absent in 121268 control chromosomes. It has been reported in a tumor cell line, however, not reported in patients. Studies assessing the impact the variant may have on the function of BRCA1 were not published at the time of classification either. Due to the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Ambry Genetics	RCV001018285	SCV001179501	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	clinical testing	The p.M1014I variant (also known as c.3042G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 3042. The methionine at codon 1014 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001867913	SCV002269056	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-01-10	criteria provided, single submitter	clinical testing	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. 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. This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 496363). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 1014 of the BRCA1 protein (p.Met1014Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001018285	SCV003849165	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).