Submissions for variant NM_007294.4(BRCA1):c.5347A>C (p.Met1783Leu)

gnomAD frequency: 0.00003  dbSNP: rs80357012

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048953	SCV000076966	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000220027	SCV000273843	likely benign	Hereditary cancer-predisposing syndrome	2019-03-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000112627	SCV000488447	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-03-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000590089	SCV000570047	uncertain significance	not provided	2016-12-16	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.5347A>C at the cDNA level, p.Met1783Leu (M1783L) at the protein level, and results in the change of a Methionine to a Leucine (ATG>CTG). Using alternate nomenclature, this variant would be defined as BRCA1 5466A>C. This variant was observed in at least one individual with diffuse large B-cell lymphoma (Björkman 2015), and functional studies have suggested no impact on BRCA1 function with respect to stability, transcription, and homology-directed repair when compared to wild type (Lee 2010, Lu 2015). BRCA1 Met1783Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Leucine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Met1783Leu occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located within the BRCT 2 domain and a region known to interact with multiple proteins (Paul 2014, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Met1783Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000048953	SCV000586910	uncertain significance	Hereditary breast ovarian cancer syndrome	2017-04-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267825	SCV000699246	uncertain significance	not specified	2024-01-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5347A>C (p.Met1783Leu) results in a conservative amino acid change in the BRCT domain (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251446 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 0.001), allowing no conclusion about variant significance. It was reported in at least one individual from an HBOC family (Judkins_2005), in a lymphoma patient (Bjorkman_2015) and several other patients either with Breast cancer or having undertaken BRCA1/2 gene testing (example, Zhang_2022, Hovland_2022), however without strong evidence for causality such as co-segregation. In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 4/60466 cases, but was also found in 3/53461 controls (Dorling_2021 through LOVD). Functional studies have demonstrated that the variant not to have any impact on HDR, transcription activation, phosphopeptide binding activity and protein stability of BRCA1 protein suggesting for neutrality (Lee_2008, Lu_2015). The following publications have been ascertained in the context of this evaluation (PMID: 25646469, 33471991, 34981296, 16267036, 20516115, 26689913, 35918668). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=4; Likely benign/Benign, n=5). Taken together, this variant is currently classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590089	SCV000887725	uncertain significance	not provided	2017-09-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220027	SCV000903153	likely benign	Hereditary cancer-predisposing syndrome	2016-07-18	criteria provided, single submitter	clinical testing
Breast Center, Key Laboratory of Carcinogenesis and Translational Research	RCV000048953	SCV001430341	benign	Hereditary breast ovarian cancer syndrome	2020-05-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267825	SCV002550943	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112627	SCV000145473	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000112627	SCV000591618	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The BRCA1 p.Met1783Leu variant has not been identified in affected individuals in the literature, but has been identified in the LOVD database, and in the BIC database 2x as a variant of unknown clinical importance. The p.Met1783 residue is not conserved in mammals and the variant amino acid Leucine is present in purple sea urchin, increasing the likelihood this variant does not have clinical significance. Computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. Two other amino acid changes at this position, p.Met1783Thr and p.Meth1483Ala were suggested to be deleterious by functional assays and predictive in silico analyses (Coyne 2004, Karchin 2007, Miyake 2000, Zhang 1998), increasing the likelihood that a change at this position is significant. However, one functional study for the variant p.Met1783Leu suggested that this specific change had no functional effect (Lee 2010), while an in silico study using functional data predicted this variant to be of unknown significance (Iversen 2011). In summary, based on the above information, the clinical significance of this variant cannot be determined at this time. Therefore, this variant is classified as a variant of unknown significance.
Brotman Baty Institute, University of Washington	RCV000112627	SCV001238211	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Center for Precision Medicine, Meizhou People's Hospital	RCV002250545	SCV002520867	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only