Submissions for variant NM_000059.4(BRCA2):c.9190G>A (p.Asp3064Asn)

gnomAD frequency: 0.00003  dbSNP: rs80359177

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083475	SCV000073755	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130150	SCV000184984	likely benign	Hereditary cancer-predisposing syndrome	2018-10-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000590167	SCV000517839	likely benign	not provided	2021-05-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25348012, 19043619, 25925381, 24817641, 29641532)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000440778	SCV000695216	likely benign	not specified	2020-10-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9190G>A (p.Asp3064Asn) results in a conservative amino acid change located in the BRCA2, OB3 domain (IPR015188) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251296 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9190G>A has been reported in the literature in patients undergoing testing without information on cancer phenotype and in the UK10K cohort of control individuals collected as part of non-cancer studies (example, Qian_2018, Pritchard_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Furthermore, a computational method that produces a probabilistic likelihood ratio has reported this variant as having a neutral outcome (Karchin_2008). At-least one co-occurrence with another pathogenic variant has been reported at our laboratory (BRCA2 c.6408_6414delAAATGTT, p.N2137fs*29), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation reporting a majority consensus towards a benign/likely benign outcome (n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was re-classified as likely benign.
Counsyl	RCV000077462	SCV000786192	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-03-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130150	SCV000911250	benign	Hereditary cancer-predisposing syndrome	2016-12-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590167	SCV002047258	likely benign	not provided	2021-04-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590167	SCV002048029	uncertain significance	not provided	2020-11-05	criteria provided, single submitter	clinical testing	The BRCA2 c.9190G>A; p.Asp3064Asn variant (rs80359177), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 52772). This variant is found on only five chromosomes (5/282678 alleles) in the Genome Aggregation Database. The aspartate at codon 3064 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.311). Due to limited information, the clinical significance of the p.Asp3064Asn variant is uncertain at this time.
Sharing Clinical Reports Project (SCRP)	RCV000077462	SCV000109260	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-03-20	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077462	SCV000147562	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000590167	SCV000778723	uncertain significance	not provided	2015-10-07	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000130150	SCV000886677	likely benign	Hereditary cancer-predisposing syndrome	2018-08-07	no assertion criteria provided	clinical testing