Submissions for variant NM_007299.4(BRCA1):c.1018C>G (p.Arg340Gly) (rs41293455)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000048522	SCV000076535	likely benign	Hereditary breast and ovarian cancer syndrome	2017-12-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129043	SCV000172955	likely benign	Hereditary cancer-predisposing syndrome	2017-12-20	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Other data supporting benign classification,In silico models in agreement (benign)
Michigan Medical Genetics Laboratories,University of Michigan	RCV000019245	SCV000195928	uncertain significance	Breast-ovarian cancer, familial 1	2014-11-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000019245	SCV000488475	benign	Breast-ovarian cancer, familial 1	2016-04-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000427206	SCV000512308	likely benign	not specified	2017-10-09	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.
Color	RCV000129043	SCV000683171	likely benign	Hereditary cancer-predisposing syndrome	2015-01-20	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000588512	SCV000699131	uncertain significance	not provided	2016-03-23	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.4327C>G variant affects a non-conserved nucleotide, resulting in amino acid change from Arg to Gly. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index); and multiple functional studies classify the variant as neutral and have shown R1443G to have comparable to wild type function (Carvalho_2007 and Bouwman_2013). This variant was found in 3/121440 control chromosomes at a frequency of 0.0000247, which does not exceed maximal expected frequency of a pathogenic BRCA1 allele (0.0010005). In addition, one clinical laboratory classified this variant as likely benign without evidence to independently evaluate. The variant has been cited in breast and ovarian cancer without evidence of causality (i.e. co-segregation data). The variant has not been reported to co-occur with other pathogenic variants in inherited cancer genes. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS)-possibly benign until additional information becomes available.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588512	SCV000885070	likely benign	not provided	2017-10-15	criteria provided, single submitter	clinical testing	The BRCA1 c.4327C>G; p.Arg1443Gly variant is published in the medical literature with a low probability of pathogenicity (Carvalho 2007, Iversen 2011, Lindor 2012). The variant is listed as benign or likely benign by several clinical laboratories in the ClinVar database (Variation ID: 17676). The variant is listed in the dbSNP variant database (rs41293455) with a low allele frequency in the Genome Aggregation Database (9/277118 alleles). The arginine at this position is weakly conserved across species and computational algorithms (AlignGVGD, PolyPhen2, SIFT) predict this variant is tolerated. Additionally, this variant is reported to behave as wild type in at least one functional assay (Bouwman 2013). Considering available information, this variant is classified as likely benign. References: Bouwman P et al. A high-throughput functional complementation assay for classification of BRCA1 missense variants. Cancer Discov. 2013 Oct;3(10):1142-55. Carvalho MA et al. Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis.Cancer Res. 2007 Feb 15;67(4):1494-501. Iversen ES Jr et al. A computational method to classify variants of uncertain significance using functional assay data with application to BRCA1. Cancer Epidemiol Biomarkers Prev. 2011 Jun;20(6):1078-88. Lindor NM et al. A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). Hum Mutat. 2012 Jan;33(1):8-21.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000588512	SCV000892186	likely benign	not provided	2018-09-30	criteria provided, single submitter	clinical testing
OMIM	RCV000019245	SCV000039533	pathogenic	Breast-ovarian cancer, familial 1	1994-12-01	no assertion criteria provided	literature only
Breast Cancer Information Core (BIC) (BRCA1)	RCV000019245	SCV000145056	uncertain significance	Breast-ovarian cancer, familial 1	2002-05-29	no assertion criteria provided	clinical testing
CSER_CC_NCGL; University of Washington Medical Center	RCV000048522	SCV000503551	uncertain significance	Hereditary breast and ovarian cancer syndrome	2016-08-01	no assertion criteria provided	research	Found in a 37 year old female patient having exome sequencing for an unrelated indication. No known history of breast cancer. Family history of a mother with breast ancer diagnosed at 50, a maternal grandmother who died of breast cancer at age 58 and a paternal grandmother diagnosed with breast and ovarian cancer.