Submissions for variant NM_007294.4(BRCA1):c.2428A>T (p.Asn810Tyr)

gnomAD frequency: 0.00006  dbSNP: rs28897682

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077518	SCV000244318	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 = 0.000000000000233
Invitae	RCV000167805	SCV000075849	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000047836	SCV000167278	benign	not specified	2014-02-26	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	RCV000162593	SCV000213011	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	RCV000077518	SCV000220977	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-12-22	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	RCV000162593	SCV000683035	benign	Hereditary cancer-predisposing syndrome	2015-12-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000047836	SCV000806915	benign	not specified	2017-10-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001356676	SCV001473091	likely benign	not provided	2020-01-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000047836	SCV002068128	likely benign	not specified	2020-05-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162593	SCV002538121	benign	Hereditary cancer-predisposing syndrome	2020-11-01	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000047836	SCV004026789	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492379	SCV004240252	likely benign	Breast and/or ovarian cancer	2022-09-27	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077518	SCV000109319	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077518	SCV000144433	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000077518	SCV000187726	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-12-10	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356676	SCV001551911	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Asn810Tyr variant was identified in 1 of 200 proband chromosomes (frequency: 0.005) from individuals or families with breast cancer (Peixoto 2006,). The variant was identified in dbSNP (rs28897682) as “with benign allele”, ClinVar (classified as benign by Invitae, GeneDx, Ambry Genetics, Color and 4 other submitters; as likely benign by Counsyl; and as uncertain significance by BIC), LOVD 3.0 (observed 15x) and UMD-LSDB (observed 19x). The variant was identified in control databases in 17 of 245,294 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 5 of 33,562 chromosomes (freq: 0.0001), European in 12 of 111,138 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The variant was observed in trans with a co-occurring pathogenic BRCA1 variant (c.3748 G>T, p.Glu1250*; Judkins 2005). Additionally, the variant was reported in the UMD-LSDB database as co-occurring with a pathogenic BRCA1 variant (c.2359dup, p.Glu787Glyfs*3). In a complementation assay in BRCA1-deficient mouse embryonic stem cells, the variant was demonstrated to have no observed effect on cell proliferation and sensitivity to cisplatin indicating the variant protein activity was sufficient to complement the BRCA1 null cells (Bouwman 2013). The p.Asn810 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.