Submissions for variant NM_000059.4(BRCA2):c.5986G>A (p.Ala1996Thr)

gnomAD frequency: 0.00003  dbSNP: rs80358833

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000195331	SCV000072826	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129689	SCV000184490	likely benign	Hereditary cancer-predisposing syndrome	2018-04-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000859013	SCV000210377	likely benign	not provided	2020-03-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30093976, 24448499, 22366370, 22752604, 28222693, 28231738, 28301460, 28993434, 31131967, 30055349, 32846166)
Illumina Laboratory Services, Illumina	RCV000077366	SCV000383729	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-27	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.
Illumina Laboratory Services, Illumina	RCV000318984	SCV000383730	likely benign	Fanconi anemia complementation group D1	2017-04-27	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044813	SCV000538488	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 3 B/LB, 2 VUS; 1 paper in HGMD
Color Diagnostics, LLC DBA Color Health	RCV000129689	SCV000910686	benign	Hereditary cancer-predisposing syndrome	2016-03-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000859013	SCV001133845	benign	not provided	2018-08-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044813	SCV001372452	likely benign	not specified	2023-10-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5986G>A (p.Ala1996Thr) results in a non-conservative amino acid change located in the BRCA2 repeat domain (IPR002093) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 251738 control chromosomes, predominantly at a frequency of 0.0037 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.5986G>A has been reported in the literature in individuals with breast/ovarian cancer (example, Juwle_2012, Kanchi_2014, Levanat_2012, Chan_2018, Darooei_2017, Lai_2017, Santonocito_2020, Wen_2018) but also, in healthy controls (e.g. Lai_2017, Wen_2018). Some of these studies report this variant with classifications ranging from VUS (Chan_2018, Darooei_2017, Wen_2018) or likely benign (Lai_2017, Harrison_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30093976, 28231738, 28301460, 22752604, 24448499, 28222693, 22366370, 32438681, 28993434). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments and a predominant consensus as benign/likely benign (n=9) (VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000195331	SCV002025790	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000044813	SCV002069977	likely benign	not specified	2019-12-11	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000195331	SCV002515128	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000129689	SCV002536196	likely benign	Hereditary cancer-predisposing syndrome	2021-05-03	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129689	SCV003850834	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).
PreventionGenetics, part of Exact Sciences	RCV003915011	SCV004745573	likely benign	BRCA2-related condition	2020-01-06	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Sharing Clinical Reports Project (SCRP)	RCV000077366	SCV000109163	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-06-05	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077366	SCV000146746	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2001-02-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000859013	SCV001744318	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000859013	SCV001906457	likely benign	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077366	SCV004243697	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing