Submissions for variant NM_007294.4(BRCA1):c.199G>T (p.Asp67Tyr)

gnomAD frequency: 0.00005  dbSNP: rs80357102

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083176	SCV000244311	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000029
Invitae	RCV000195312	SCV000075688	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148404	SCV000190103	uncertain significance	Breast and/or ovarian cancer	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx	RCV000047675	SCV000209902	likely benign	not specified	2017-08-28	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000162582	SCV000212998	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000083176	SCV000220787	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-13	criteria provided, single submitter	literature only
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000195312	SCV000324827	uncertain significance	Hereditary breast ovarian cancer syndrome	2015-08-27	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000047675	SCV000586866	likely benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000047675	SCV000588027	benign	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589035	SCV000698905	benign	not provided	2017-07-03	criteria provided, single submitter	clinical testing	Variant summary: This missense variant involves the alteration of a non-conserved nucleotide and 3/5 in silico tools predict a pathogenic outcome. The variant is present at a low frequency in the control population (0.0076% in ExAC, 0.012% in European (Non-Finnish)), and has been reported in the literature in HBOC patients and families. Most of these publications, however, fail to provide co-segregation and co-occurrence data, and do not test for large deletions/insertions, and therefore do not provide strong evidence for the causality of this variant. In addition, one report, although a poster presentation, is provided by individuals from a reputable laboratory, Myriad, indicating the variant was found to co-occur with 9 pathogenic variants (gene and variants not specified) and was classified as benign. UMD lists variant in 15 individuals with classification of "1-Neutral". One of them carried a pathogenic BRCA2 variant c.1773_1776delTTAT (p.Ile591MetfsX22). Furthermore, several functional studies have been published and showed that the c.199G>T variant had a moderate effect on centrosome duplication (Kais_2012, Towler_2013), chromosomal instability, (Cochran_2015), and resulted in a moderate reduction in E3 ligase activity, but that the mutant protein had similar binding of BRCA1 to BARD1 (Caleca_2014, Ransburgh_2010, Morris_2006, Starita_2015) and wild-type levels of E2 interaction (Morris_2006). There was no difference in homologous recombination (Kais_2012, Ransburgh_2010), double strand break repair by the single-strand annealing pathway (Towler_2013), yeast colony size, spot formation, and yeast localization (Thouvenot_2016) between mutant BRCA1 with this variant and wild-type BRCA1. This variant also had no effect on splicing via patient cDNA and minigene splicing assay (Houdayer_2012, Thery_2011). Additionally, multifactorial probability based models showed a low odds in favor of causality (Lindor_2012, Easton_2007). In addition, multiple reputable databases, UMD, ARUP, and clincial labs classify the variant as "benign/likely benign, at-least 2 of whom have submitted/updated their submissions to ClinVar since the time of the previous classification of this variant in our laboratory." Therefore, taking all evidence into consideration, the variant of interest is classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589035	SCV000883466	likely benign	not provided	2017-08-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162582	SCV000902756	likely benign	Hereditary cancer-predisposing syndrome	2016-07-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000083176	SCV001287533	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2018-04-24	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Sema4, Sema4	RCV000162582	SCV002538078	likely benign	Hereditary cancer-predisposing syndrome	2021-08-26	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002490619	SCV002803126	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-08-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083176	SCV000115250	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2007-03-07	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083176	SCV000144627	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353503	SCV000591248	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Asp67Tyr variant was identified in 4 of 1760 proband chromosomes from individuals or families with breast or ovarian cancer (Blay 2013, Diez 2003); however, control chromosomes from healthy individuals were not evaluated in these studies. The variant was also identified HGMD, LOVD, the BIC database (8X with unknown clinical importance), and UMD (15X as a neutral variant). In UMD, the variant was found to co-occur with a pathogenic BRCA2 mutation (c.1773_1776delTTAT (p.Ile591MetfsX22)) in one sample, increasing the likelihood that the p.Asp67Tyr variant may not have clinical significance. The variant was listed in dbSNP (ID: rs80357102) “With allele of Uncertain significance”, with a minor allele frequency of 0.0005 (1000 Genomes Project), and in the NHLBI Exome Sequencing Project (Exome Variant Server) in 2 of 8582 European American alleles; however the low number and frequency of this variant in these populations is not substantive enough to determine the prevalence of this variant in the general population. This residue is not conserved in mammals and lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Several function studies found the variant to have a neutral effect on BRCA1 function, including assays evaluating protein binding, homology directed recombination, and single-strand annealing repair (Atipairin 2011, Bouwman 2013, Caleca 2014, Morris 2006, Ransburgh 2010, Towler 2013). One study found that the variant had an intermediate effect on centrosome amplification; however, the authors suggest that this may be on the high end of the normal range (Kais 2012). In addition, two in silico studies using multifactorial probability based models found this variant to be neutral (Easton 2007, Lindor 2012). Furthermore, Myriad classifies this variant as “Favor polymorphism” (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Brotman Baty Institute, University of Washington	RCV000083176	SCV001241658	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
King Laboratory, University of Washington	RCV000047675	SCV001251392	benign	not specified	2019-09-01	no assertion criteria provided	research
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000047675	SCV001931360	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000047675	SCV001957784	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000047675	SCV001974493	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000083176	SCV004244184	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing