Submissions for variant NM_007294.4(BRCA1):c.3411G>A (p.Met1137Ile)

gnomAD frequency: 0.00001  dbSNP: rs786202900

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165959	SCV000216716	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-18	criteria provided, single submitter	clinical testing	The p.M1137I variant (also known as c.3411G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 3411. The methionine at codon 1137 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is not well 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.
Invitae	RCV000197284	SCV000254973	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-02-24	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. This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1137 of the BRCA1 protein (p.Met1137Ile). This variant is present in population databases (rs786202900, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 186375). 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.
Counsyl	RCV000410247	SCV000489037	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165959	SCV000912038	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-14	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 1137 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA1-related disorders in the literature. This variant has been identified in 2/282406 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165959	SCV003850379	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).