Submissions for variant NM_000059.4(BRCA2):c.4376A>G (p.Asn1459Ser)

gnomAD frequency: 0.00001  dbSNP: rs117187202

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044400	SCV000072413	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000166927	SCV000217746	likely benign	Hereditary cancer-predisposing syndrome	2019-07-01	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.
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240790	SCV000265940	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Counsyl	RCV000031479	SCV000487988	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000481899	SCV000568107	uncertain significance	not provided	2023-02-06	criteria provided, single submitter	clinical testing	Observed in individuals with breast or ovarian cancer (Suter 2004, Chao 2016, Zhong 2016, Lai 2017, Li 2017, Chen 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 4604A>G; This variant is associated with the following publications: (PMID: 14973102, 28664449, 31131967, 27257965, 28222693, 27907908, 27157322, 31867841, 30702160, 31825140, 32467295, 29884841, 32377563)
3DMed Clinical Laboratory Inc	RCV000677823	SCV000803983	uncertain significance	Invasive lobular breast carcinoma	2017-02-27	criteria provided, single submitter	clinical testing
3DMed Clinical Laboratory Inc	RCV000677824	SCV000803984	uncertain significance	Ovarian cancer	2017-02-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166927	SCV000911008	likely benign	Hereditary cancer-predisposing syndrome	2021-09-03	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000166927	SCV003850463	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003234931	SCV003933861	likely benign	not specified	2023-05-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4376A>G (p.Asn1459Ser) results in a conservative amino acid change located in the BRCA2 repeat region (IPR002093), located between repeat 3 and 4 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 4.3e-05 in 276508 control chromosomes, exclusively reported within the East Asian subpopulation at a frequency of 0.0006 (in the gnomAD v2.1 dataset). This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome (0.00075), allowing no clear conclusions about variant significance. The variant, c.4376A>G, has been reported in the literature in individuals of East Asian origin affected with breast- or ovarian cancer (Lai_2017, Bhaskaran_2019), but was also found in several unaffected East Asian controls (Lai_2017, Momozawa_2018, Dong_2021). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 7/60466 cases, but was also found in 9/53461 controls (Dorling_2021, reported through LOVD). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a large scale study utilizing multifactorial probability model for quantitative analysis of BRCA1 and BRCA2 variants predicted this variant to be likely benign (Parsons_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31131967, 28222693, 30287823, 30702160, 32467295, 33471991). Eight submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as VUS (n=5) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV000031479	SCV004845676	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031479	SCV000054084	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2009-12-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031479	SCV000146415	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-09-18	no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250488	SCV002520790	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only