Submissions for variant NM_000059.3(BRCA2):c.6101G>A (p.Arg2034His) (rs80358849)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166225	SCV000217004	likely benign	Hereditary cancer-predisposing syndrome	2018-11-19	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);Other strong data supporting benign classification
Counsyl	RCV000083122	SCV000487876	uncertain significance	Breast-ovarian cancer, familial 2	2015-11-24	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000166225	SCV000903931	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 2034 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). The presence of histidine as the reference amino acid in multiple other mammals suggests this variant may be benign. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer in the literature (PMID: 9971877, 17333343, 28435519, 30086788, 30415210), however a multifactorial likelihood analysis of breast cancer patients demonstrated a posterior probability indicating the variant is likely benign (PMID: 30415210). This variant has been identified in 1/250974 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina	RCV001110580	SCV001268032	uncertain significance	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina	RCV000083122	SCV001268033	uncertain significance	Breast-ovarian cancer, familial 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV001374119	SCV001570896	uncertain significance	Hereditary breast and ovarian cancer syndrome	2020-09-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 2034 of the BRCA2 protein (p.Arg2034His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs80358849, ExAC 0.002%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 17333343, 28435519). ClinVar contains an entry for this variant (Variation ID: 52012). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ITMI	RCV000120341	SCV000084493	not provided	not specified	2013-09-19	no assertion provided	reference population
Sharing Clinical Reports Project (SCRP)	RCV000083122	SCV000115196	uncertain significance	Breast-ovarian cancer, familial 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083122	SCV000146769	uncertain significance	Breast-ovarian cancer, familial 2	2004-02-20	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529429	SCV001742886	likely benign	not provided		no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV001529429	SCV001951592	likely benign	not provided		no assertion criteria provided	clinical testing