Submissions for variant NM_007294.4(BRCA1):c.889A>C (p.Met297Leu)

dbSNP: rs80357196

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000496473	SCV000586874	likely benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000111492	SCV000786454	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2018-05-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775184	SCV000909398	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with leucine at codon 297 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with breast cancer and one suspected hereditary breast and ovarian cancer family (PMID: 27062684, 30254663, 32380732, 34178674). This variant has not been identified 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.
Invitae	RCV001348061	SCV001542349	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-06-23	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. 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. ClinVar contains an entry for this variant (Variation ID: 55741). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 15235020, 27062684, 30254663, 34178674). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 297 of the BRCA1 protein (p.Met297Leu).
Ambry Genetics	RCV000775184	SCV002686200	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-12	criteria provided, single submitter	clinical testing	The p.M297L variant (also known as c.889A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 889. The methionine at codon 297 is replaced by leucine, an amino acid with highly similar properties. This alteration was reported in trans with a BRCA1 pathogenic mutation based on haplotype analysis in a patient with breast and/or ovarian cancer who underwent clinical genetic testing, and was classified as a variant of unknown significance (Judkins T et al. Cancer Res. 2005 Nov;65(21):10096-103). In a study of 1854 high-risk breast/ovarian cancer families in Italy, this alteration was detected in one family (Azzollini J et al. Eur. J. Intern. Med., 2016 Jul;32:65-71). This alteration was also observed in 1 of 1045 Italian patients with breast and/or ovarian cancer fulfilling established criteria for HBOC genetic testing (Zuntini R et al. Front Genet, 2018 Sep;9:378). 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.
GeneDx	RCV003105786	SCV003761772	uncertain significance	not provided	2022-07-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 1008A>C; Observed in individuals with breast and/or ovarian cancer (Azzollini et al., 2016; Zuntini et al., 2018; Fanale et al., 2021); This variant is associated with the following publications: (PMID: 31131967, 27062684, 16267036, 15235020, 34178674, 30254663, 20215511, 15343273, 9788437, 9926942, 9582019)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000775184	SCV003847869	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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111492	SCV000143934	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000111492	SCV004228324	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-01	no assertion criteria provided	clinical testing	PM2(Supporting)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)