Submissions for variant NM_007294.4(BRCA1):c.1511G>A (p.Arg504His)

gnomAD frequency: 0.00004  dbSNP: rs56272539

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111637	SCV000244305	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 = 0.00000106
Invitae	RCV001086247	SCV000075520	benign	Hereditary breast ovarian cancer syndrome	2024-01-19	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148409	SCV000190108	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	RCV000590149	SCV000209928	likely benign	not provided	2020-12-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32548945, 30287823, 18779604, 22753008, 9333265, 21990134, 17924331, 26543556, 16014699, 20858050, 15235020, 25637381, 24728327)
Ambry Genetics	RCV000162973	SCV000213461	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: 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	RCV000111637	SCV000220533	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-07-22	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590149	SCV000698871	benign	not provided	2016-03-25	criteria provided, single submitter	clinical testing	Variant Summary: The c.1511G>A variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.007% (8/121170), which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA1 (0.10%). However, the frequency data should still suggest that this variant is likely to be a rare polymorphism. The variant has been reported to co-occur with many deleterious pathogenic variants in BRCA1, such as c.70_80del (8 times in BIC), c.78_79insCATCTG (1 time in BIC) and p.Ser510Ter (1 time in BIC). A publication (Tavtigian_2006) also reported co-occurrence with an unspecified deleterious BRCA1 variant in six samples. (Presence of a variant in trans with another deleterious variant in BRCA1 is a definite evidence of benign outcome and thus it is very likely that the reported co-occurrence information is in line with this notion.) Studies presenting multifactorial probability based models report the variant as a neutral variant (Easton_2007, Lindor_2012). In addition, multiple reputable databases/clinical diagnostic laboratories have classified the variant as neutral/likely benign/benign. Taken together, this variant is classified as Benign.
Color Diagnostics, LLC DBA Color Health	RCV000162973	SCV000902715	benign	Hereditary cancer-predisposing syndrome	2016-11-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000111637	SCV001140600	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000111637	SCV001287422	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-04-28	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.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001086247	SCV002026000	benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120287	SCV002071360	likely benign	not specified	2021-08-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162973	SCV002538036	likely benign	Hereditary cancer-predisposing syndrome	2021-10-22	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000148409	SCV003838246	likely benign	Breast and/or ovarian cancer	2022-02-16	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000111637	SCV004016785	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590149	SCV004140632	likely benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	BRCA1: BP1, BP2
ITMI	RCV000120287	SCV000084439	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111637	SCV000144120	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000120287	SCV000587146	benign	not specified	2014-01-31	no assertion criteria provided	research