Submissions for variant NM_007294.4(BRCA1):c.2050C>T (p.Pro684Ser)

gnomAD frequency: 0.00001  dbSNP: rs397508934

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000047694	SCV000075707	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130395	SCV000185254	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-24	criteria provided, single submitter	clinical testing	The p.P684S variant (also known as c.2050C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2050. The proline at codon 684 is replaced by serine, an amino acid with similar properties. This alteration was observed in individuals diagnosed with breast and pancreatic cancer (Lee AS et al. Hum Mutat. 2003; 22:178; Lu W et al. Fam Cancer, 2012 Sep;11:381-5; Grant RC et al. Gastroenterology, 2015 Mar;148:556-64). This amino acid position is 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768616	SCV000324813	uncertain significance	Breast and/or ovarian cancer	2023-01-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000586501	SCV000568423	uncertain significance	not provided	2023-02-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as 2169C>T; This variant is associated with the following publications: (PMID: 12872263, 27376475, 28726806, 31131967, 33087888, 34981296, 15343273)
Department of Pathology and Molecular Medicine, Queen's University	RCV000485811	SCV000588037	uncertain significance	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130395	SCV000688363	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-10	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 684 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). This variant has been reported in individuals affected with breast and/or ovarian cancer and in suspected hereditary breast and ovarian cancer families (PMID: 12872263, 22476429, 27376475, 34981296) and an individual affected with pancreatic cancer (PMID: 25479140). This variant also 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_006467). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.1026 and 0.0665, respectively (PMID: 31131967). This variant has been identified in 1/251296 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000485811	SCV000698912	uncertain significance	not specified	2023-05-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2050C>T (p.Pro684Ser) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. A report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as likely benign (class 2) in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). The variant allele was found at a frequency of 4e-06 in 251396 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2050C>T has been reported in the literature as a VUS in individuals affected with Pancreatic, Breast and/or Ovarian Cancer and within settings of multigene panel testing for hereditary cancers (e.g. Lu_2012, Grant_2015). A large scale multifactorial probability based analysis classified this variant as IARC class 2 (likely benign, Parsons_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22476429, 24728327, 25479140, 12872263, 27376475, 31131967, 31112341, 33087888, 34981296). Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=7) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Fulgent Genetics, Fulgent Genetics	RCV000764123	SCV000895096	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000485811	SCV002068948	uncertain significance	not specified	2018-03-27	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130395	SCV003849542	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).