Submissions for variant NM_007294.4(BRCA1):c.3247A>C (p.Met1083Leu)

gnomAD frequency: 0.00006  dbSNP: rs397507213

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164913	SCV000215601	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-03	criteria provided, single submitter	clinical testing	The p.M1083L variant (also known as c.3247A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 3247. The methionine at codon 1083 is replaced by leucine, an amino acid with highly similar properties. This variant was observed in an individual with early onset-breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). 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.
Invitae	RCV000559848	SCV000635890	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-08	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 37517). 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. 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 missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 18092194, 25186627). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1083 of the BRCA1 protein (p.Met1083Leu). This variant is present in population databases (rs397507213, gnomAD 0.003%).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590619	SCV000699009	uncertain significance	not provided	2016-10-03	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.3247A>C (p.Met1083Leu) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). Met1083 is not conserved across species and is not located in a known functional domain.This variant was found in 2/121344 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Counsyl	RCV000031098	SCV000784960	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-02-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164913	SCV000909313	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-08	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with leucine at codon 1083 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 been reported in one individual affected with breast cancer (PMID: 25186627) and members of a suspected hereditary breast and ovarian cancer family (PMID: 18092194). This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006343). This variant has been identified in 4/281890 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.
GeneDx	RCV000590619	SCV001993608	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25186627, 18092194)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164913	SCV003849019	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).
Sharing Clinical Reports Project (SCRP)	RCV000031098	SCV000053694	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2009-06-16	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031098	SCV004244060	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing