Submissions for variant NM_007294.3(BRCA1):c.2525A>G (p.Glu842Gly) (rs28897684)

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077109	SCV000244322	benign	Breast-ovarian cancer, familial 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 = 0.0000043
Ambry Genetics	RCV000162977	SCV000213465	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing
Invitae	RCV000168463	SCV000219162	likely benign	Hereditary breast and ovarian cancer syndrome	2017-12-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000077109	SCV000487935	benign	Breast-ovarian cancer, familial 1	2015-12-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000430143	SCV000512294	likely benign	not specified	2017-08-15	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.
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000430143	SCV000591394	likely benign	not specified	2016-03-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000430143	SCV000600293	likely benign	not specified	2017-03-10	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000430143	SCV000698965	likely benign	not specified	2019-04-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2525A>G (p.Glu842Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251106 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2525A>G was originally reported in the literature in individual(s) affected with Hereditary Breast and Ovarian Cancer (Judkins_2005). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. The variant has been reported in the FLOSSIES database in two women older than age 70 years who have never had cancer, providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Studies utilizing multifactorial likelihood models to assess the clinical significance of BRCA1 variants predict this variant to be neutral/not pathogenic (Lindor_2012, Easton_2007). Six ClinVar submissions from clinical diagnostic laboratories and an expert panel (ENIGMA) (evaluation after 2014) cite the variant as likely benign (4x) and twice as benign. All submitters have utilized the same/overlapping sources of evidence utilized in this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Color	RCV000162977	SCV000911835	benign	Hereditary cancer-predisposing syndrome	2016-11-21	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077109	SCV000108906	benign	Breast-ovarian cancer, familial 1	2012-05-01	no assertion criteria provided	clinical testing